Angelman Syndrome and the 15q11-q13 Region

Literature and regulatory information updated: 6 October 2026.

Maternal deletion, paternal uniparental disomy, imprinting defects, UBE3A variants and mosaic forms; maternally derived 15q duplication syndrome (dup15q); 15q11.2 BP1-BP2 microdeletion (Burnside-Butler syndrome)

0. Initial Reference Table

Table 0 summarises the identifiers and quantitative parameters of the three entities grouped in this article, which share the same genomic architecture of the proximal long arm of chromosome 15 but differ in mechanism, clinical expression and counselling [1–8].

1. Introduction

In 1965, the English paediatrician Harry Angelman described three unrelated children with severe intellectual disability, a stiff, jerky gait, characteristic facial features and frequent paroxysms of laughter, whom he called “puppet children” because their movements evoked those of puppets [9, 10]. The designation “happy puppet syndrome” spread over the following decades, until Williams and Frias delineated the condition's natural history and proposed abandoning the term, which was considered inappropriate [10, 11]. Angelman syndrome (AS) is now defined as a genetic neurobehavioural disorder resulting from loss of function of the UBE3A gene at 15q11.2-q13, which is expressed solely from the maternal allele in neurones [1, 12].

The molecular history of AS is intertwined with the discovery of human genomic imprinting. In 1989, Knoll and colleagues demonstrated that AS and Prader-Willi syndrome (PWS) share a common chromosome 15 deletion but differ in the parental origin of the deleted chromosome, maternal in AS and paternal in PWS [13]. This finding provided the first clinical demonstration that genes within the same chromosomal segment are expressed differently according to the parent of origin, a phenomenon known as genomic imprinting [10, 14]. This was followed by the identification of paternal uniparental disomy (UPD) of chromosome 15 and imprinting centre defects and, in 1997, the simultaneous demonstration by two groups that pathogenic loss-of-function variants in UBE3A, which encodes ubiquitin ligase E3A (E6-AP), cause AS [15, 16]. In 2006, the Scientific Advisory Committee of the Angelman Syndrome Foundation (USA) updated the consensus clinical criteria, which remain in use [17], and in 2019 the European Molecular Genetics Quality Network (EMQN) and the Association for Clinical Genomic Science (ACGS) published updated recommendations for the molecular diagnosis of PWS and AS [18].

The same chromosomal region gives rise to two other entities addressed in this article. Maternally derived 15q duplication syndrome (dup15q) results from one or more additional copies, inherited from the mother, of the Prader-Willi/Angelman critical region (PWACR), either as an isodicentric supernumerary marker chromosome, idic(15) or inv dup(15), or as an interstitial duplication; idic(15) is the most frequent supernumerary marker chromosome in humans [2, 10, 19]. Microdeletion of 15q11.2 between breakpoints BP1 and BP2 was associated with intellectual disability, learning difficulties and behavioural disorders by Doornbos and colleagues in 2009 [20, 21]; in 2011, Burnside and colleagues, studying a large cohort with deletions and duplications of the same region, proposed that this was a susceptibility region for neurological dysfunction with reduced penetrance [22], and the eponymous designation Burnside-Butler syndrome became established in subsequent literature [5, 23].

Current clinical interest in these conditions extends beyond diagnosis: AS has become a model for therapies that reactivate the silenced paternal UBE3A allele using antisense oligonucleotides (ASOs), with three molecules in clinical development and phase 3 trials under way in 2026, one of which has already concluded with a negative result [24–27], while the BP1-BP2 microdeletion has become a paradigm for susceptibility copy number variants (CNVs), whose interpretation requires estimates of penetrance and effect size [8, 28].

2. Molecular Genetics and Pathophysiology

2.1 Genomic architecture of 15q11-q13

The proximal long arm of chromosome 15 contains five blocks of segmental duplications, or low copy repeats (LCRs), designated breakpoints BP1 to BP5, which predispose to rearrangements through non-allelic homologous recombination (NAHR) [2, 22]. The PWACR lies between BP2 and BP3 and contains exclusively paternally expressed genes (including MAGEL2, NDN, SNURF-SNRPN and the HBII-85 small nucleolar RNA cluster, or SNORD116) and UBE3A, which is maternally expressed in neurones, whereas the distal segment contains biallelically expressed genes, including those encoding three GABA-A receptor subunits (GABRB3, GABRA5, GABRG3), OCA2 and HERC2 [1, 2, 29, 30]. The BP1-BP2 segment, approximately 500 kb in size, contains four conserved, non-imprinted genes, TUBGCP5, CYFIP1, NIPA1 and NIPA2 [21, 22].

Typical AS and PWS deletions span 5 to 7 Mb and extend from BP1 (class I, approximately 6 Mb) or BP2 (class II, approximately 5 Mb) to BP3; fewer than 10% of deletions extend more distally to BP4 or BP5 [1, 6]. Class I deletions therefore include the BP1-BP2 segment, and Butler's review of the BP1-BP2 microdeletion emphasises that people with AS or PWS and a class I deletion have greater clinical severity than those with a class II deletion, although GeneReviews considers it uncertain whether the two groups can be distinguished clinically in AS [1, 23]. Microdeletions flanking the typical region (BP1-BP2, BP3-BP4 and 15q13.3 between BP4 and BP5) do not produce the AS phenotype [1].

2.2 Imprinting and regulation of UBE3A

Genomic imprinting is the mechanism whereby genes are selectively silenced on the maternal or paternal homologue, so that only one allele is expressed according to parental origin; the epigenetic mark, chiefly DNA methylation established during gametogenesis, is maintained throughout life and reprogrammed in germ cells [14]. In the 15q11-q13 region, the imprinting centre (IC) has a bipartite structure: the PWS critical element (PWS-SRO, approximately 4.3 kb, overlapping the promoter and exon 1 of SNURF-SNRPN) and the AS critical element (AS-SRO, approximately 880 bp, located 35 kb upstream of exon 1 of SNURF-SNRPN) [1].

UBE3A has a 5' CpG island without differential methylation between alleles; its imprinting is indirect. On the paternal allele, a long SNURF-SNRPN sense/UBE3A antisense RNA (UBE3A-ATS), over 460 kb long, is transcribed from the SNURF-SNRPN promoter, extending at least to the 5' end of UBE3A and blocking expression of the paternal allele in neurones [1]. Both alleles are expressed in other tissues [1]. This organisation has two clinical consequences: only loss of the maternal allele causes AS, and the structurally intact paternal allele is a potential therapeutic target, providing the rationale for ASO strategies directed against UBE3A-ATS [24, 25].

The E6-AP protein is an E3 ubiquitin ligase that receives ubiquitin from an E2 enzyme and transfers it to substrates destined for proteasomal degradation, including ARC, LAMTOR1, BMAL1, RAD23A/B, MCM7 and CDKN1B; it thereby participates in activity-dependent synaptic development and remodelling, mTORC1 signalling, the circadian clock and protein quality control [1, 31]. The ubiquitin-proteasome pathway is involved in signal transduction, the cell cycle, DNA repair and transcriptional regulation; its dysfunction in neurones explains a deficiency without a peripheral biochemical marker [1]. The hypopigmentation observed with deletions results partly from hemizygosity of OCA2, a pigmentation gene located at 15q11-q13, but modulation of melanocortin 1 receptor (MC1R) activity by UBE3A also appears to contribute [1]. When a 15q11-q13 deletion removes one copy of OCA2 and the other chromosome 15 carries a pathogenic OCA2 variant, oculocutaneous albinism associated with AS may occur [30].

2.3 Molecular classes of Angelman syndrome

Table 1 integrates the frequencies of AS molecular classes according to different sources; the differences reflect the period and method of each series.

The frequencies are derived from [1, 10, 12, 32–34]. The French PNDS (French National Diagnosis and Care Protocol) gives different values in its introduction and in its genetics chapter, attributes a size of about 4 Mb to the typical deletion and assigns 15% of cases to UBE3A variants; this article retains the 5-7 Mb and the approximately 11% given by GeneReviews and the EMQN/ACGS recommendations, which are based on series with complete molecular characterisation [1, 18, 34]. Class Ia deletions are overwhelmingly de novo; a proportion of mothers of children with class II deletions (BP2-BP3) carry genomic inversions at 15q11-q13 that predispose to germline deletion, and families with an inherited inverted intrachromosomal insertion resulting in AS, PWS and 15q11-q13 duplication within the same family have been described [1]. Maternal germline mosaicism for large 15q11-q13 deletions has been documented, including a Finnish family, a Spanish family with affected dizygotic twins and a Chinese family [12, 35, 36].

In AS, unlike PWS, paternal UPD more often has a postzygotic origin (for example, duplication of paternal chromosome 15 after loss of the maternal chromosome), whereas a meiotic origin is less common [1, 37]. It may also result from trisomy or monosomy rescue, and paternal isodisomy arising through monosomy rescue has been described in an individual whose mother carried a Robertsonian translocation (14;15) [1, 12]. The French PNDS reports significantly increased maternal and paternal ages in cases of paternal UPD, which is consistent with meiotic non-disjunction followed by fertilisation of an oocyte nullisomic for chromosome 15 and duplication of the paternal chromosome [34].

Imprinting defects cause maternal chromosome 15, although present, to have a paternal epigenotype and to be transcriptionally incompetent for maternally expressed genes [1, 14]. More than 90% are primary epimutations occurring during oogenesis or early embryogenesis, without an IC deletion; fewer than 10% of individuals with an imprinting defect have a small, transmissible AS-SRO deletion [1]. A pair of siblings with AS and a 1-1.5 Mb inversion separating the two IC elements without a deletion has been described [1].

UBE3A variants (over 250 described) include small frameshift deletions and duplications, missense, nonsense and splicing variants, large deletions and complex rearrangements [1]. Approximately 30% are inherited from asymptomatic mothers who received them from their fathers [1]. Interpretation follows the ClinGen Rett and Angelman-like Disorders Expert Panel specifications for the ACMG/AMP recommendations (version 6.0.0); because the gene is imprinted, demonstration of paternal inheritance of a variant of uncertain significance (VUS) allows it to be reclassified as benign [1]. No alteration is identified in approximately 10% of people with a clinical diagnosis of AS; possible explanations include an incorrect clinical diagnosis, undetected variants in UBE3A regulatory regions or other genes involved in UBE3A function [1].

2.4 Mosaic forms

Mosaicism in AS occurs predominantly in imprinting defects without an IC deletion: approximately 20% of these individuals have somatic mosaicism, with one population of normally methylated cells and another with a paternal epigenotype [1, 38]. In the SNRPN methylation assay, these patients show only a faint maternal band [12]. The proportion of normal cells determines the phenotype, which is milder and sometimes atypical, with hypotonia, hyperphagia and a larger head circumference, potentially leading to an initial diagnosis of PWS [12, 39]. Maternal somatic and germline mosaicism for UBE3A variants has also been described, with implications for recurrence risk [1, 40].

2.5 Genotype-phenotype correlations in Angelman syndrome

All molecular classes produce severe to profound intellectual disability, movement disorder, characteristic behaviour and severe language impairment, but severity varies [1, 41]. The 5-7 Mb deletion produces the most severe phenotype, with microcephaly, epilepsy, motor difficulties (ataxia, hypotonia, feeding difficulties), greater language impairment, hypopigmentation and a lower body mass index [1, 42, 43]. Paternal UPD and imprinting defects are associated with less frequent epilepsy, better motor development and a greater tendency towards obesity; OXF describes cytogenetic deletions as the most severe and UPD as the least severe, whereas GeneReviews states that individuals with UBE3A variants or imprinting defects may be less affected than those with UPD, reflecting the overlap between non-deletion groups [1, 12]. Truncating UBE3A variants appear more severe than missense variants [41]. Individuals with mosaic imprinting defects have the most advanced language skills, with up to 50-60 words and simple sentences [1, 38]. In the Danish study, the mean age at diagnosis was 21 months for deletions and 46 months for paternal UPD or UBE3A variants [6].

2.6 Maternal 15q duplication syndrome

The diagnosis of maternal dup15q requires at least one additional maternally derived copy of the PWACR, a region of approximately 5 Mb between BP2 and BP3 (approximately chr15:22,782,170-28,134,728, GRCh38) [2]. The two main mechanisms are the supernumerary isodicentric chromosome idic(15), usually bisatellited, with two mirror-image copies of 15pter-q13.1, which causes 15q11.2-q13.1 tetrasomy (≈ 60-80%) and is thought to result from a U-type exchange during maternal meiosis; and interstitial duplication, through NAHR between BP1 or BP2 and BP3, which causes trisomy (≈ 20-40%) [2, 10]. Variations on these mechanisms include interstitial triplication (tetrasomy), hexasomy through complex isodicentric chromosomes, asymmetric triplications (15q11.2-q13.2 tetrasomy with 15q13.2-q13.3 trisomy, in 10-15% of cases) and supernumerary ring chromosomes, usually mosaic [2]. idic(15) is associated with increased maternal age and is mostly of maternal origin; the severity of developmental impairment is proportional to the number of additional copies and the extent of the duplicated region [44]. Small chromosome 15 markers without the PWACR have no phenotypic effect and constitute the most common “benign” marker [10, 44].

Increased dosage of UBE3A, expressed from the maternal allele in neurones, is considered the main cause of intellectual disability, anxiety, a reduced seizure threshold and some autistic features; transgenic mice overexpressing UBE3A have learning deficits, anxious behaviour and a low seizure threshold [2, 10]. The GABA-A subunit genes (GABRB3, GABRA5, GABRG3) are implicated in epilepsy and the characteristic electroencephalographic pattern, with excessive beta activity (12-30 Hz), similar to that induced by midazolam in typically developing children [2]. HERC2 expression is increased in neurones from individuals with dup15q [2]. Paternal duplications of the same region have a more variable, less penetrant phenotype [2, 45]. The French PNDS adds that the rearrangements range from about 4.5 to 12 Mb (from BP1-BP3 to BP1-BP5), that the supernumerary material may be present in five (pentasomy) or six (hexasomy) copies, or more, that the duplicated region contains about twenty genes, including MAGEL2, UBE3A, ATP10A, GABRB3, GABRA5 and GABRG3, and that severity correlates with the number of extra copies and, in mosaic forms, with the proportion of carrier cells; it also stresses that no single gene explains the phenotype on its own, a reading compatible with the main, but not exclusive, role of UBE3A overdosage [46].

2.7 15q11.2 BP1-BP2 microdeletion

The BP1-BP2 microdeletion is a recurrent 300-500 kb CNV that removes TUBGCP5 (a component of the gamma-tubulin ring complex, required for microtubule nucleation), CYFIP1 (a component of the WAVE regulatory complex, promoting actin polymerisation, and an inhibitor of translation together with FMRP protein and eIF4E), NIPA1 and NIPA2 (magnesium transporters expressed in the brain) [5, 22, 23]. ClinGen classifies haploinsufficiency of NIPA1 alone as having no evidence, so the CNV phenotype is not attributed to loss of NIPA1 itself; dominant-negative NIPA1 variants, particularly at the hotspot c.316G>A/C (p.Gly106Arg; NM_144599.5, MANE Select transcript), cause a distinct entity, autosomal dominant hereditary spastic paraplegia type 6 (SPG6, OMIM 600363), which must not be confused with the microdeletion [28, 47, 48]. A parent-of-origin effect has been described: in 71 individuals with known inheritance, maternal deletions were associated with macrocephaly, epilepsy and autism spectrum disorder (ASD), and paternal deletions with congenital heart disease and muscle abnormalities [49].

3. Clinical Spectrum and Manifestations by System

3.1 Angelman syndrome: core features

All people with classic AS have four features: severe developmental delay, profound speech impairment, a movement and balance disorder (a wide-based ataxic gait and/or limb tremor), and a behavioural profile with an apparently happy disposition, frequent laughter and smiling, excitability and hand-flapping movements [1, 12, 17]. Pregnancy, delivery and head circumference at birth are usually normal, and there are no major malformations [1, 12]. Developmental delay becomes apparent at around six months, but distinctive features only become evident after the first year [1]. Table 2 brings together the frequencies of the principal manifestations.

Data from [1, 10, 12, 50].

3.2 Neurological manifestations

Epileptic seizures usually begin between one and three years of age (peaking between 18 and 24 months), may occur at any age and mostly present by five years [1, 10, 12]. The most frequent types are myoclonic, atonic, generalised tonic-clonic and atypical absence seizures; up to 50% have multiple seizure types, and infantile spasms are rare [1, 51]. Epilepsy is more severe in early childhood (Smith reports peak severity at around four years), may diminish or disappear in late childhood and recur in adulthood [10, 12]. Non-convulsive status epilepticus (NCSE), particularly of the atypical absence or myoclonic type, may go unnoticed and manifest as reduced alertness, loss of skills, head drops, hypotonia or myoclonus lasting hours or days [1]. Non-epileptic, or cortical, myoclonus consists of sudden movements resembling tics or jerks, without impaired consciousness or an electroencephalographic correlate, and predominates in adolescents and young adults [1].

The French PNDS describes the course of the epilepsy in greater detail. Seizures occur in about 90% of patients, usually begin between one and two years of age, sometimes in a febrile context, and atonic seizures, myoclonic seizures and atypical absences predominate; tonic seizures and fast rhythms during sleep, typical of Lennox-Gastaut syndrome, are as a rule absent. In the initial phase, resistance to the first and second drug is common, and more than half of children have episodes of status epilepticus, sometimes with repeated hospital admissions; in the second decade, about two thirds become seizure-free and one third discontinue treatment, but some series describe a resurgence in adulthood, with up to 90% of adults still having seizures, and the PNDS estimates active epilepsy in adults at about 40%, with improvement in 60% of those who had epilepsy in childhood. In adults, myoclonic seizures and absences predominate, and these may worsen or appear de novo, together with myoclonic or absence status epilepticus, tonic-clonic seizures and, more rarely, atonic and focal occipital seizures. Epilepsy in deletion cases is generally more severe, whereas in UBE3A variant cases monotherapy usually controls the seizures; an earlier age at onset has been associated with autism spectrum disorder, irrespective of molecular class. SUDEP is not excluded, but the PNDS regards it as exceptional in AS [34].

Myoclonic or absence status epilepticus presents with loss of contact, subtle or subcontinuous myoclonus, worsening ataxia and coordination, and apathy; episodes may last hours or days, with a risk of falls and aspiration, sometimes resolve spontaneously, and are triggered by severe constipation, infection or the introduction of a pro-epileptogenic drug. Diagnosis rests on electroclinical correlation by video-EEG and, when the nature of the episodes is uncertain, the response to a buccal, sublingual or rectal benzodiazepine can serve as a diagnostic test. When epilepsy begins in the first year, the presentation may mimic West syndrome, and review of the electroclinical recordings avoids inappropriate treatment; tremor of the extremities must be distinguished from epileptic myoclonus, and some authors have described its worsening with valproate [34].

The electroencephalogram (EEG) has diagnostic value. Characteristic patterns include bursts of high-amplitude delta activity (2-3 Hz) with intermittent spikes and slow waves (sometimes with a notched delta appearance), diffuse rhythmic theta activity and rhythmic sharp theta activity at 5-6 Hz in the posterior regions, facilitated by or visible only with eye closure [1, 10]. The EEG may be abnormal even without a history of seizures, and a normal EEG does not exclude the diagnosis [12]. According to the PNDS, these patterns are constant before 10 years of age: bifrontal 2-3 Hz delta activity may persist into adulthood, continuous 4-6 Hz theta activity disappears at around 12 years, and the abundance of interictal abnormalities, in wakefulness and sleep, should not be mistaken for hypsarrhythmia in infants; the cortical origin of the erratic myoclonus, without a correlate on conventional EEG, has been demonstrated by back-averaging [34]. Brain magnetic resonance imaging (MRI) is structurally normal or shows mild atrophy and delayed myelination [1, 10].

Limb tremor may be noticeable before 12 months and is associated with brisk tendon reflexes [1]. Axial hypotonia occurs with increased limb tone [12]. The mean age at acquisition of sitting is 12 months, and independent walking is acquired at a mean age of four years, between 2.5 and 6 years; in a Dutch cohort of 100 children, walking began at a mean of 58 months with deletions and 41 months with the other classes [1, 12, 43]. In the most severe cases, the gait is stiff, “robotic” and wide-based, with raised and flexed arms, bent elbows, pronated forearms and hands at shoulder level [1, 12, 33]. Approximately 10% do not acquire independent walking [1, 10]. Voluntary movements are irregular, ranging from slight jerks to coarse, uncoordinated movements that hinder reaching for objects, feeding and walking [1]. Parkinsonism and dystonia may develop in adulthood, described at around 50 years [33]. The PNDS adds that about one third of adults use a wheelchair, that loss of mobility results from limb hypertonia, contractures, scoliosis and reduced motivation to move, and that crouch gait, with short, hypertonic hamstrings and secondary equinus due to Achilles tendon shortening, is common from adolescence onwards [34].

3.3 Communication, cognition and behaviour

Most individuals do not acquire speech or use only 2-3 words; in a survey of 47 individuals, 39% said up to four words, and in another series 13% had five or more words [1, 12]. Receptive language and non-verbal communication always exceed expressive language [1, 10]. Most older children and adults communicate by pointing, gesturing and using communication boards or picture exchange communication systems (PECS); some master signing systems such as Makaton, although fluent use of sign language does not occur [1, 12]. Rare patients acquire more than 200 words [12]. Psychometric tests suggest a developmental level between 24 and 30 months, probably underestimated because of language limitations and hyperactivity [1].

Laughter occurs more often in social situations (speech, touch, eye contact from adults) and decreases in non-social contexts; it may be an appropriate response to humour or non-specific stimuli, or an expression of anxiety [1, 10, 12]. Virtually all young children have hyperactivity, persistent oral exploration, chewing and mouthing of objects, fascination with water, reflections and noisy materials (paper, plastic), increased heat sensitivity and abnormal eating behaviours [1, 10, 12]. Aggressive or self-injurious behaviours (pinching, grabbing, biting, hitting) chiefly reflect attention seeking and communication frustration [1]. Despite some traits suggestive of ASD, social engagement is usually good and classic stereotypies are rare; some people respond to applied behaviour analysis (ABA) [1]. The SGRT table additionally includes bruxism, drooling, self-injury, attention deficit hyperactivity disorder (ADHD) and enuresis [33]. Anxiety increases with age, whereas sleep disturbances tend to improve [10, 52].

The data compiled by the French PNDS detail the communication profile. Speech is absent or almost absent in more than 70% of people with AS; when words are present, vocabulary ranges from 2 to 15, with a mean of five and approximate articulation, and the expressive level rarely reaches that of a typically developing one-year-old, although a minority reach about a hundred words. Comprehension lies between the 5-month and 24-month levels, with wide variability and probable underestimation by standardised scales. About 75% reach for objects out of reach, 40-55% use deictic gestures such as pointing, half use signs (usually fewer than ten) and, in North American surveys, about half use a tablet with voice output, with benefit reported in about 70%; skills are better in non-deletion forms and continue to progress in adulthood, without cognitive deterioration with age [34]. Separation anxiety from a family caregiver affects about 40%, especially adolescents and adults. A meta-analysis cited by the PNDS estimated the prevalence of autism spectrum disorder at 34%, with 50-81% in deletion cases, which diverges from the GeneReviews reading of good social engagement and justifies early specialist assessment in children with a deletion; in a learning study, 50% of children with a deletion responded to sensory reinforcement and 28% to social reinforcement, compared with 14% and 85% of children without a deletion, which requires behavioural programmes to be individualised [1, 34].

3.4 Sleep, the digestive system, growth and other systems

Sleep disturbances include frequent and early awakenings, dyssomnias, fragmented sleep-wake cycles, nocturnal periods of laughter and sleep-related seizures, exacerbated by constipation, reflux and scoliosis; the reduced need for sleep is most marked between 2 and 6 years [1, 10]. In infancy, sucking is ineffective because of oropharyngeal incoordination; approximately 50% have feeding difficulties, particularly with deletions, and 10-15% require a nasogastric tube or gastrostomy [1, 12, 50]. Gastro-oesophageal reflux disease (GORD) affects 45-65%, persists throughout life and requires treatment to prevent oesophagitis and upper gastrointestinal bleeding [1, 50]. Vomiting may be cyclic (more frequent with deletions and UPD) or intermittent, and constipation, common at any age, may cause behavioural changes, weight loss, poorer sleep and increased seizures [1]. Hyperphagia and problematic eating behaviours occur in 20-50% across all classes, and obesity is more frequent in non-deletion classes [1, 12]. Persistent tongue protrusion affects 30-50%, and drooling is treated conservatively, since salivary gland surgery and scopolamine patches have limited efficacy [1].

The French PNDS describes sensory and somatic features little covered by the other sources. There is impaired thermoregulation, increased heat sensitivity and excessive sweating, and hyperthermia, even moderate, lowers the seizure threshold; the response to pain appears delayed and attenuated in parental questionnaires, so a sudden behavioural change or the onset of aggression should prompt a search for pain (reflux, constipation, teeth, orthopaedic complications). About 70% of infants have feeding difficulties, GORD may cause serious pulmonary complications, and final height is generally below target height, with food impulsivity similar to that of PWS but less intense. Iron deficiency is more frequent in AS and is associated with periodic limb movements in sleep [34]. The oral phenotype includes maxillary and mandibular underdevelopment, macroglossia, a high-arched palate, Angle class II malocclusion with anterior open bite, bruxism, periodontal disease favoured by salivary stasis with the mouth open, an increased risk of caries, delayed shedding of primary teeth and dental trauma from seizures and falls; antiseizure medications may cause xerostomia and gingival hyperplasia [34]. Refractive error is the most frequent ocular abnormality (97%), more severe in deletion cases, and keratoconus appears in adulthood; according to the PNDS, ocular hypopigmentation occurs in all three genetic subgroups and not only in deletion cases, which diverges from the consensus criteria [17, 34]. Scoliosis and lumbar hyperlordosis have been recorded in 14-35% and flat feet with inversion in about 60%; in a group of 18 patients, almost half had osteopenia, associated with low physical activity and the duration of antiseizure medication, particularly valproate. Menarche occurs at a mean age of 12.4 years, with usually regular cycles; premenstrual symptoms (irritability, aggression, crying, anxiety) and menstrual symptoms (dysmenorrhoea, headache, diarrhoea) are common, treated with non-steroidal anti-inflammatory drugs in 60% and with hormonal contraception in 31%, and 38% of women with epilepsy have catamenial epilepsy [34].

Growth at birth is normal; mean height in childhood is below that of the population, but final height is generally normal, with an increased weight-to-height ratio, particularly without deletion [1]. Most individuals have a head circumference below the 25th centile at three years, but severe microcephaly is unusual, and individuals with mosaic imprinting defects have a larger head circumference [12, 30]. In addition to strabismus (approximately 30% require surgery), astigmatism (the most common refractive error), keratoconus (possibly due to eye rubbing), myopia, hypermetropia, nystagmus, optic nerve pallor or atrophy, chorioretinal atrophy, ptosis and amblyopia are described; ocular hypopigmentation affects the iris and choroid [1, 10, 33]. Puberty is usually normal (early menarche in 17% and late menarche in 27%), and fertility appears preserved; transmission of a 15q11.2-q13 deletion by a woman with AS has been documented [1]. Orthopaedic features, in addition to thoracic scoliosis, include lumbar hyperlordosis (20-25% of adults), hip dysplasia, valgus or pronated ankles, Achilles tendon shortening, progressive joint contractures and low bone mineral density, more frequent during antiseizure medication use, with reports of increased fracture risk [1, 12].

3.5 Mosaic form (mosaic imprinting defect)

The phenotype of mosaic imprinting defects differs from the classic phenotype: children may have up to 100 words and speak in sentences, ataxia and seizures may be absent, most do not have microcephaly, and hyperphagia with obesity is common, leading to initial diagnoses of PWS or non-specific intellectual disability [12, 39, 53]. A series including patients with mosaic AS considered preserved expressive language a phenotypic determinant of this form [1].

3.6 Maternal 15q duplication syndrome

Maternal dup15q is characterised by hypotonia and motor delay, intellectual disability, ASD and epilepsy, including infantile spasms; it is rarely associated with psychosis or sudden death [2]. idic(15) is more severe than interstitial duplication, but severity varies between individuals with the same mechanism [2, 19]. Table 3 compares the two groups.

Data from [2, 54, 55].

Neonatal hypotonia is associated with feeding difficulties, gross motor delay and constipation; most individuals acquire walking after two to three years, earlier in the interstitial form, often with an ataxic or wide-based gait [2]. Language delay is universal, ranging from moderate to severe, with echolalia, pronoun reversal and stereotyped expressions or absence of functional speech, and most function within the moderate to severe intellectual disability range [2, 19]. Maternal dup15q is the CNV associated with the greatest risk of ASD (odds ratio ≥ 2.6), but children with dup15q retain responsive social smiling and facial expressions directed towards others, a feature distinguishing them from non-syndromic ASD [2, 55].

More than half have epilepsy, usually with multiple seizure types (infantile spasms, myoclonic, tonic-clonic, absence, focal), beginning between six months and nine years [2, 54]. dup15q is one of the most frequent known genetic causes of infantile spasms; up to 40% of patients with epilepsy initially present with spasms, and approximately 90% of these subsequently develop other seizure types, frequently Lennox-Gastaut syndrome [2, 54]. Intractable epilepsy may cause falls and regression in more than half of cases with frequent seizures or NCSE [2]. Dysmorphic features are subtle (flat occiput, downslanting palpebral fissures, epicanthic folds, depressed nasal bridge, a short nose with an upturned tip, low-set ears, long philtrum, high palate, thick lips, micrognathia) [2, 45]. Hyperactivity, anxiety and emotional lability have been described, as have schizophrenia and strabismus in carriers of large markers [2, 10]. Psychosis is underrecognised, possibly because of diagnostic difficulties in people with cognitive and verbal impairment; psychosis is also frequent in PWS due to maternal UPD, which likewise entails two maternal copies of 15q11.2-q13.1 [2, 21]. Sudden unexpected death in epilepsy (SUDEP) affects a significant minority, almost always during sleep, particularly adolescents and young adults with epilepsy; inability to walk and poor seizure control are risk factors [2, 56]. Penetrance is 100% for idic(15) and appears complete for interstitial duplication, although some carriers have mild manifestations [2]. The French PNDS adds gastrointestinal disorders (swallowing difficulties, GORD, constipation, aspiration) in 87% of interstitial duplications and 76% of idic(15) cases, sensory disturbances (auditory hypo- or hyper-responsiveness, texture selectivity, altered pain threshold), obsessive-compulsive disorder, self-injury and aggression; diagnosis is usually made at around 3-4 years, and almost half of patients have infantile spasms before one year of age (at a mean of six months), associated with myoclonus and rarely with typical hypsarrhythmia, on a background of development already abnormal before the spasms [46].

3.7 15q11.2 BP1-BP2 microdeletion

The phenotype described in clinical series includes developmental delay (73%) and speech delay (67%), writing (60%) and reading difficulties (57%), memory problems (60%), verbal IQ ≤ 75 (50%), behavioural abnormalities (55%), abnormal brain imaging (43%), motor delay (42%), dysmorphic ears and palatal abnormalities (46% each), ADHD (35%), ASD (27%), epilepsy (26%) and schizophrenia or paranoid psychosis (20%) [5]. In a large series, approximately 87.5% of deletion carriers and 80% of reciprocal duplication carriers had developmental delay or intellectual disability; hypotonia, heart disease and skeletal abnormalities have also been described [21, 22]. These frequencies, however, derive from clinically referred populations: in the meta-analysis by Jønch and colleagues, the deletion reduces IQ by 4.3 points and confers odds ratios of 1.7 for intellectual disability (frequency of 3.4% in carriers), 1.5 for schizophrenia (2%) and 3.1 for epilepsy (2.1%), without increasing the risk of ASD or heart disease; among referred carriers, the nature and frequency of symptoms did not differ from those observed in carriers of the 15q11.2 duplication, used as a neutral control, indicating ascertainment bias [28]. The CNV is therefore considered a susceptibility variant with incomplete penetrance and variable expressivity [21, 22, 57]. A 2026 report described a child with a 258 kb maternal 15q11.2 deletion, classified as likely pathogenic, with myoclonic absence seizures and electroencephalographic findings that the authors likened to AS biomarkers; this is an isolated case that does not alter penetrance estimates or, on its own, justify diagnostic confusion with AS, which requires methylation testing [58].

4. Clinical Recognition and Red Flags

In AS, clinical recognition relies on a combination of signs that is rarely complete before two years. An infant with hypotonia, sucking difficulties and non-specific psychomotor delay may be misdiagnosed with cerebral palsy, static encephalopathy or mitochondrial disease; limb tremor and jerky movements help distinguish AS from these conditions [1]. Red flags include global delay with absent speech disproportionate to comprehension; deceleration of head circumference growth, particularly if mild microcephaly develops in the first year, before seizures and the characteristic facial appearance; seizures beginning between 18 and 24 months; an EEG with high-amplitude delta slow waves at 2-3 Hz, even without seizures; readily provoked laughter and excitability with hand flapping; a stiff, ataxic gait with raised arms; relative hypopigmentation compared with family members; and fascination with water [1, 10, 12, 30]. An EEG with AS features should prompt a full molecular investigation, including testing for UBE3A variants [30]. Absence of regression distinguishes AS from Rett syndrome [1, 30]. The French PNDS stresses that the ready smiling, present from 1-3 months, does not correspond to an appropriate social response, that provoked laughter may appear from 10 weeks, and that head circumference growth decelerates until it stabilises at around −2 SD by about one year; the first seizure frequently occurs with fever. Family members and staff of medico-social facilities should know the signs of non-convulsive status epilepticus (apathy, loss of contact, subcontinuous myoclonus, worsening ataxia), which requires urgent contact with the referring physician [34].

During history taking, a three-generation pedigree seeks other affected individuals consistent with maternal transmission, suggesting a UBE3A variant, an IC deletion or a chromosomal rearrangement [12]. A child with hypotonia, hyperphagia, normal or increased head circumference and relatively preserved language, with a methylation assay suggesting only a faint maternal band, should raise suspicion of mosaic AS [12, 39]. An infant with a 15q11.2-q13 deletion on CMA, hypotonia and feeding difficulties should not be labelled as having PWS without confirmation of parental origin through methylation analysis [1].

In dup15q, red flags include moderate to severe hypotonia with early motor delay, ASD with preserved social smiling, infantile spasms or difficult-to-control epilepsy, and an EEG with excessive beta activity; detection of a bisatellited supernumerary marker chromosome on karyotyping should prompt characterisation of the PWACR [2, 44, 45]. Inability to walk and poor seizure control identify patients at greater risk of SUDEP, which almost always occurs during sleep [2, 56]. There are no specific clinical signs for the BP1-BP2 microdeletion; its identification is almost always a finding on CMA performed for developmental delay, ASD, epilepsy or prenatal ultrasound abnormalities [5, 59]. Prenatally, dup15q is rarely detected, because there are no specific ultrasound signs; it may emerge from CMA requested for fetal growth restriction or another ultrasound anomaly, or from targeted testing when there is a family history [46].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Consensus clinical criteria (2005) for Angelman syndrome

Adapted from [1, 17]. A clinical diagnosis can be established on the basis of these criteria, and molecular diagnosis requires demonstration of deficient expression or function of the maternal UBE3A allele in a proband with suggestive findings [1].

5.2 Laboratory methods

Adapted from [1, 18, 33]. In a normal individual, the SNRPN methylation assay shows one methylated allele (maternal) and one unmethylated allele (paternal); in deletions, UPD and imprinting defects, only the unmethylated allele is present, whereas patients with UBE3A variants and those in class V have normal methylation [1, 12]. Southern blot methods, historically used, have fallen out of use because of cost [33].

5.3 Diagnostic algorithm for Angelman syndrome

The algorithm recommended by GeneReviews, OXF and the EMQN/ACGS recommendations follows four steps [1, 12, 18]. First, in cases of clinical suspicion without previous investigations, 15q11.2-q13 methylation analysis is the first-line test. Second, if methylation is abnormal, the mechanism is identified, which is essential for counselling: CMA (or FISH) for deletion; if there is no deletion and the array does not show segmental or complete isodisomy, chromosome 15 DNA polymorphism testing in the proband and parents to exclude heterodisomy; and, once UPD is excluded, an imprinting defect is presumed and an IC deletion is sought. Third, if methylation is normal and the presentation is typical, UBE3A sequencing followed by targeted deletion/duplication analysis; alternatively, a multigene panel (epilepsy, ASD, intellectual disability) including UBE3A and the differential diagnosis genes. In a series of sporadic patients with normal methylation, UBE3A sequencing had a yield of 44%; UBE3A variants are identified in 80% of familial cases and 15% of sporadic cases [12]. Fourth, in cases with negative results or an atypical phenotype, exome or genome sequencing (possibly with mitochondrial sequencing) and CMA, because other chromosomal abnormalities mimic AS [1, 12]. In an individual in whom a 15q11.2-q13 deletion has been found by CMA, FISH or karyotyping, methylation analysis determines whether the deletion is maternal (AS) or paternal (PWS) [1]. In mild phenotypes with suspected mosaicism, methylation must be interpreted in a broader clinical context, and quantitative methods are necessary to detect low-level mosaicism [39, 53]. DNA storage is recommended for probands without a molecular diagnosis [1]. The French PNDS accepts two first-line strategies: starting with SNRPN methylation or with FISH or CMA, a rapid approach that confirms the diagnosis and the mechanism in deletion cases (more than 65% of cases) and may reveal UPD; if both are negative and clinical suspicion is strong, UBE3A sequencing follows. It also recommends systematic confirmation of the de novo nature of deletions by maternal karyotype and FISH and accepts, in class V, a diagnosis based on clinical findings alone [34].

5.4 Diagnosis of dup15q

Oligonucleotide or SNP CMA detects 100% of duplications that include the PWACR and allows their size to be estimated, but does not reliably distinguish idic(15) from an interstitial triplication; FISH or karyotyping is needed to determine whether the duplication is supernumerary or interstitial and to detect mosaicism, which has been described in idic(15) as a result of mitotic instability [2]. idic(15) and large interstitial duplications (> 5 Mb) are visible on karyotyping; smaller interstitial duplications are not [2]. Maternal origin is confirmed by genotyping, by methylation analysis (including PCR-based methods) or by identifying the duplication in the mother [2]. Targeted methods (FISH, qPCR, MLPA) are used to test relatives but not to diagnose a proband without prior CMA [2]. When a supernumerary marker is found, OXF recommends characterising it by array (or, if unavailable, by its G-banding pattern and the presence of a centromere and satellites), studying the parents' karyotypes with a 30-cell screen for mosaicism and initiating UPD studies if the marker contains euchromatin from an imprinted region [44]. The French PNDS follows the same pathway: CMA is the diagnostic test, qPCR, FISH and MLPA are used for confirmation and family studies, karyotyping distinguishes idic(15) from interstitial triplication (both showing four copies on CMA) and parental origin is determined by MS-MLPA or microsatellite markers; in paternal duplication, the phenotype is variable and generally milder, with ASD in fewer than 50% and parasomnias. Before attributing the presentation to an interstitial duplication, especially a severe one, another chromosomal or genic cause of intellectual disability should be excluded [46].

5.5 Interpretation of the BP1-BP2 microdeletion

The microdeletion is detected by CMA in 0.57-1.27% of patients tested, two to four times the frequency in controls [5]. In the analysis by Rosenfeld and colleagues, the 15q11.2 deletion (NIPA1; chr15:20.3-20.8 Mb, hg18) was found in 203/25,113 (0.81%) cases and 84/22,246 (0.38%) controls, with 0/27 de novo cases and estimated penetrance of 10.4% (95% CI 8.45-12.7%) [8, 57, 60]. Jønch and colleagues recommend classification as “pathogenic of mild effect” and consider that, because it explains a small fraction of phenotypic variance, it does not warrant in-depth discussion in developmental consultations or the prenatal setting [28]. OXF notes that some laboratories do not routinely report CNVs with substantial incomplete penetrance in prenatal diagnosis [57]. When the deletion is found in a child with a more severe phenotype, a second cause should be sought: a case published in 2025 associated an ASXL3 variant and the BP1-BP2 microdeletion with a severe phenotype [61], and OXF recommends considering unmasking of a recessive allele, imprinting, incomplete penetrance, complex inheritance or expansion of a parental duplication when there is a phenotypic discrepancy between parent and child [57].

5.6 Limitations of genetic tests and report content

Each method answers a different question, and a negative result excludes only what the method can detect. Methylation analysis identifies approximately 80% of AS cases but does not detect UBE3A variants or class V and does not distinguish between deletion, UPD and an imprinting defect; MS-MLPA adds dosage analysis but does not separate UPD from an epimutation; SNP CMA detects deletions and isodisomy but not heterodisomy, balanced translocations or inversions; and qualitative assays may fail to detect low-level mosaic imprinting defects, which require quantitative methods [1, 18, 39, 53]. UBE3A sequencing does not detect deletions of one or more exons or, generally, deep intronic or regulatory variants, justifying targeted deletion/duplication analysis and, in a typical phenotype with negative results, DNA storage and subsequent reanalysis [1]. Exome sequencing or a multigene panel does not replace methylation analysis, because it does not detect epigenetic changes and, in most configurations, also does not detect UPD [1, 18].

Three protein numbering systems coexist for UBE3A: that of isoform 1 (NP_570853.1, 852 amino acids), that of isoform 2 (NM_000462.5/NP_000453.2, 875 amino acids), used by GeneReviews and much of the literature, and that of isoform 3 (NM_130839.5/NP_570854.1, 872 amino acids), which corresponds to the MANE Select transcript; the three differ only at the amino-terminal end, so the same residue has numbers differing by 20 or 23 positions depending on the reference isoform [62, 63]. The report should therefore state the gene, versioned transcript, HGVS c. and p. nomenclature, zygosity, parental origin when studied, ACMG/AMP classification according to the ClinGen expert panel specifications, and method limitations; when an article uses historical numbering, it is helpful to present both. Parental origin carries particular weight in this region: a UBE3A variant inherited from the father does not cause AS, and the panel specifications permit this demonstration to be used to classify a VUS as benign, but inheritance from an asymptomatic mother is expected when she received the variant from her father and does not, on its own, prove pathogenicity [1]. A VUS should not be reclassified on the basis of response to treatment or partial segregation in a few relatives; testing parents and other relatives is described as investigation until formal reclassification by the laboratory.

In dup15q, the report should state ISCN nomenclature with the reference genome version, copy number, whether the duplication is interstitial or supernumerary (CMA does not reliably distinguish idic(15) from an interstitial triplication), any mosaicism and parental origin, which determines interpretation [2]. In the BP1-BP2 microdeletion, the report should present it as a susceptibility CNV with incomplete penetrance, accompanied by available estimates, and avoid automatic causal attribution [8, 28]; NIPA1 point variants associated with SPG6, a different entity, are described using NM_144599.5, whose numbering matches that in the original description of p.Gly106Arg [48, 62].

6. Differential Diagnosis

Conditions mimicking AS share absent speech, severe intellectual disability, epilepsy and sometimes a happy demeanour; many were reviewed by Tan and colleagues [1, 64]. Table 6 summarises the principal conditions.

Data from [1, 12, 33, 64, 65]. OXF recommends CMA in children with an AS phenotype without a 15q11-q13 abnormality [12]. The French PNDS focuses the differential diagnosis on the other rare genetic neurodevelopmental disorders, notably Pitt-Hopkins and Rett syndromes, and points out two electroclinical pitfalls: epilepsy beginning in the first year may mimic West syndrome, and abundant interictal abnormalities should not be read as hypsarrhythmia [34].

The differential diagnosis of mosaic AS includes PWS and non-specific intellectual disability with hyperphagia and obesity [12, 39]. The dup15q phenotype is insufficiently specific for clinical diagnosis, and the differential includes all chromosomal abnormalities and genes associated with intellectual disability; paternal duplications of the same region, PWS (a distinct phenotype, with speech and a mean IQ of 60-70), AS, 15q13.3 (BP4-BP5) and BP1-BP2 deletions, and 15q11.2 or 15q13.3 duplications without the PWACR (considered of uncertain significance) are genetically related entities [2]. Because the BP1-BP2 microdeletion is frequent and has low penetrance, it coexists with other causes, and investigation for a second aetiology (exome sequencing, high-resolution CMA, fragile X testing) remains indicated for a moderate or severe phenotype [28, 57].

7. Treatments and Risk Management Strategies

7.1 Angelman syndrome: initial assessment and symptomatic treatment

There are no international guidelines for AS based on a systematic review; the only national protocol identified is the French Protocole National de Diagnostic et de Soins (PNDS) of the Haute Autorité de Santé (HAS), dated December 2021, developed by expert consensus among the reference centres together with the patient association. As of October 2026, there is no disease-modifying therapy approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA), and management is symptomatic and multidisciplinary [1, 25, 34]. Following diagnosis, recommendations include neurological assessment with EEG and brain MRI; assessment of motor, adaptive and cognitive development and non-verbal communication, with referral for early intervention and special education; screening for behavioural and sleep disturbances; gastroenterological and nutritional assessment (reflux, nutritional status); ophthalmological examination (strabismus, ocular albinism, visual acuity); orthopaedic and physical medicine assessment (scoliosis, ankle pronation or subluxation, Achilles tendon shortening, hypotonia, need for assistive devices); genetic counselling and assessment of family and social support needs [1]. The child should be followed by a multidisciplinary child development team, and preschool stimulation programmes such as Portage have an important role [12]. The PNDS adds to the initial assessment systematic hearing evaluation (repeated in the event of recurrent otitis), assessment of adaptive behaviour with the Vineland scale, the Dunn sensory profile, the paediatric pain profile in children followed by professionals and, in deletion cases, early assessment for autism spectrum disorder; it recommends assessing pain with adapted scales (GED-DI or rFLACC for acute pain; EDAAP in institutionalised adults), without the scale replacing the judgement of caregivers. The diagnosis should be disclosed progressively, in a protected setting, preferably with both parents, followed by a second consultation and psychological support, with the contact details of patient associations provided [34].

Adapted from [1, 12].

According to clinical surveys, the antiseizure medications most often used as the first approach in AS are clobazam, levetiracetam, lamotrigine and clonazepam; others (brivaracetam, cenobamate, felbamate, gabapentin, lacosamide, pregabalin, rufinamide, tiagabine, cannabidiol) have minimal data, and a parental survey suggested less benefit with phenobarbital, primidone, carbamazepine, phenytoin, valproic acid and vigabatrin [1, 51]. Doses follow the approved labels, and none of these indications is specific to AS. For focal seizures, levetiracetam (Keppra®) is started, according to the FDA label, at 7 mg/kg twice daily from 1 to < 6 months (up to 21 mg/kg twice daily), at 10 mg/kg twice daily from 6 months to < 4 years (up to 25 mg/kg twice daily) and from 4 to < 16 years (up to 30 mg/kg twice daily, maximum 3000 mg/day), with increases every two weeks, and from 16 years at 500 mg twice daily up to 1500 mg twice daily; in the European SmPC, from 6 months to 17 years with body weight < 50 kg, 10 mg/kg twice daily with increases of 10 mg/kg twice daily every 2 weeks up to 30 mg/kg twice daily (the 25 mg/kg twice-daily maximum from 6 months to < 4 years appears only in the US label), and with ≥ 50 kg 500 mg twice daily (or 250 mg twice daily for the first 2 weeks) up to 1500 mg twice daily [66]; the most relevant adverse effects are somnolence, asthenia and behavioural changes (irritability, aggression), which require monitoring in this population [67]. Clobazam (Onfi®, Frisium®) is FDA-approved as adjunctive therapy for Lennox-Gastaut syndrome from two years of age: with body weight ≤ 30 kg it is started at 5 mg/day up to 20 mg/day, and with body weight > 30 kg at 10 mg/day up to 40 mg/day, in two divided doses above 5 mg/day, with titration no faster than weekly; adverse effects include somnolence, drooling, ataxia and a risk of dependence and withdrawal syndrome, so discontinuation must be gradual [67]. Non-epileptic myoclonus is difficult to treat; levetiracetam, clobazam and clonazepam have been used, with one report of success with perampanel [1]. Diazepam may be used for outpatient treatment of NCSE [1].

More recent data do not change the empirical nature of this choice. In a retrospective natural history cohort from the Munich Angelman centre, comprising 101 children seen between 2019 and the first quarter of 2025, 75% had epilepsy, more frequently with deletions; epilepsy was refractory in 34% of children with seizures, also with a higher proportion among those with deletions, and the three most prescribed drugs (ethosuximide, valproate and levetiracetam) had response rates, defined as a greater than 50% reduction in seizures, of 78%, 75% and 64%, without differences in serious adverse effect rates between them [68]. A 2026 expert opinion review considers levetiracetam and clobazam the preferred first-line drugs and valproate and clonazepam effective, but with a more complex adverse effect profile [69]. These sources differ from the 2009 parental survey, which suggested less benefit from valproate [51]; all are observational or opinion-based, and response rates from a referral centre cohort are not comparable between drugs, because drug choice depends on seizure type, age and severity.

All people with AS and a history of seizures should have rescue medication for prolonged seizures: rectal diazepam gel, intranasal midazolam or intranasal diazepam [1]. Intranasal diazepam (Valtoco®) is FDA-approved for seizure clusters from two years of age, at a dose of 0.5 mg/kg from 2 to 5 years, 0.3 mg/kg from 6 to 11 years and 0.2 mg/kg from 12 years, with a possible second dose after at least four hours, up to two doses per episode, no more than one episode every five days and no more than five episodes per month; intranasal midazolam (Nayzilam®) is approved from 12 years of age, 5 mg into one nostril with a second 5 mg dose into the opposite nostril after 10 minutes if there is no response, up to two doses per episode and no more than one episode every three days; both carry a risk of respiratory depression, particularly with other central nervous system depressants [67]. Rectal diazepam gel (FDA label, seizure clusters) is dosed by age: 0.5 mg/kg from 2 to 5 years, 0.3 mg/kg from 6 to 11 years and 0.2 mg/kg from 12 years, rounding up to the next available dose unit (units of 2.5 to 20 mg; 20 mg is the largest unit, corresponding to 36-44 kg from 2 to 5 years, 59-74 kg from 6 to 11 years and 88-111 kg from 12 years); a second dose, if needed, is given 4-12 hours after the first, and the label recommends treating no more than five episodes per month and one episode every five days [70]. In the EU, oromucosal midazolam (Buccolam®) is given as a single age-based dose: 2.5 mg from 3 months (in a hospital setting up to 6 months) to < 1 year, 5 mg from 1 to < 5 years, 7.5 mg from 5 to < 10 years and 10 mg from 10 years into adulthood; if the seizure does not stop within 10 minutes, urgent medical assistance is sought, and a second dose is given only on medical advice [66].

Two practices should be avoided: excessive treatment with sedative drugs to attenuate hyperexcitability and hyperactivity, and excessive antiseizure medication when abnormal movements are mistaken for seizures or electroencephalographic abnormalities persist despite clinical control [1]. In refractory forms, the ketogenic diet or low glycaemic index treatment has benefited some patients [1].

The French PNDS organises antiseizure therapy differently from the North American surveys. There is no preventive measure before the first seizure beyond teaching the family to recognise it; once epilepsy is confirmed, long-term maintenance treatment is started with paediatric neurology follow-up, and the aim is seizure control, not normalisation of interictal abnormalities. Broad-spectrum drugs active against absences and myoclonus are chosen (sodium valproate, benzodiazepines, levetiracetam, topiramate, lamotrigine), as initial monotherapy and in combination if this fails; valproate is the drug most often used first-line in France, a small retrospective series found similar efficacy for valproate, topiramate, levetiracetam and lamotrigine, with monitoring for tremor on valproate, and ethosuximide has a place for absences and myoclonus. In cortical myoclonus, benefit has been described with benzodiazepines, levetiracetam, ethosuximide and piracetam, the latter at high dose, effective against myoclonus and with possible improvement in motor function. Benzodiazepines are effective but rarely first-line, because they cause excitation or somnolence, worsening ataxia and bronchial hypersecretion, and they are reserved for acute episodes or combination therapy; experience with zonisamide, rufinamide, perampanel and eslicarbazepine is limited, and behavioural and weight tolerance should be reassessed shortly after each new drug is introduced [34].

The PNDS considers vigabatrin and tiagabine contraindicated and advises caution with carbamazepine, oxcarbazepine, lacosamide and, by analogy, eslicarbazepine, which may worsen generalised seizures, absences and myoclonus or induce non-convulsive status epilepticus. In drug resistance, after excluding an aggravating drug, a somatic factor causing decompensation and confusion with non-epileptic phenomena, the ketogenic diet and vagus nerve stimulation have shown benefit in isolated observations. Follow-up assesses adherence (with level monitoring for drugs that can be measured: valproate, carbamazepine, phenytoin, phenobarbital, lamotrigine), efficacy by seizure diary and use of rescue medication, and clinical and, depending on the drug, laboratory tolerance. For seizures lasting more than five minutes or recurring, a conditional prescription of buccal midazolam or rectal diazepam is provided to the parents, with caregiver training (safety, severity criteria, calling the emergency number); non-convulsive status epilepticus with moderate impairment of consciousness may be treated with an oral benzodiazepine for a few days, with gradual tapering, and established status epilepticus requires hospital admission and an intravenous benzodiazepine. Information on triggers (fever, sleep deprivation), showering instead of bathing, care with sleeping position and individualised precautions during risky activities are also recommended [34]. In girls and women, valproate prescribing follows the pregnancy prevention programme of the SmPC [71].

In catamenial epilepsy, control was achieved by increasing the antiseizure medication dose in 57% and with hormonal treatment in 43%. The PNDS mentions natural progesterone, 100-200 mg/day orally or vaginally, given cyclically (a few days before menstruation for perimenstrual seizures, or from day 15 of the cycle for luteal-phase seizures in anovulatory cycles), injectable medroxyprogesterone and continuous combined oestrogen-progestogen, whereas synthetic progestogens, particularly the norsteroids, are of little or no efficacy. Epilepsy does not contraindicate contraception, but enzyme inducers (phenobarbital, primidone, phenytoin, carbamazepine, felbamate, topiramate above 200 mg/day, rufinamide, oxcarbazepine) reduce the efficacy of hormonal contraceptives, so, according to the Société Française de Neurologie recommendations cited in the PNDS, progestogen-only contraception and low-dose combined oestrogen-progestogen are avoided and a non-hormonal method is proposed first-line; conversely, combined oestrogen-progestogen can reduce lamotrigine concentrations by up to 50%, so the neurologist must be informed in order to adjust the dose [34]. A gynaecology consultation should systematically be offered to young women, for the management of menstruation and catamenial epilepsy; in the absence of sexual activity, gynaecological examination and cervical cytology are not recommended, and breast screening follows that of the general population [34].

Table 7D brings together the doses of the drugs mentioned by the PNDS that are not included in the interventions table or in the preceding text; where the PNDS gives no dose, the official label is used and the extrapolation is indicated.

For sleep, the PNDS recommends first excluding medical factors (nocturnal epilepsy, GORD, iron deficiency, obstructive apnoea, periodic limb movements), with polysomnography when apnoea, periodic limb movements, nocturnal epilepsy or complex parasomnia is suspected, and with iron studies; parental psychoeducation and behavioural interventions (a dark, quiet and cool environment, no screens, a bedtime routine and regular schedules) are first-line, and pharmacological treatment is added when these are insufficient. Children with AS have low nocturnal melatonin and, in cases with phase delay, a delayed peak; low-dose immediate-release melatonin can advance the sleep phase, and the prolonged-release formulation is preferable when difficulty falling asleep and awakenings coexist, although no child with AS was included in the paediatric pivotal trial [34, 66].

When faced with challenging behaviour, the PNDS directs a search for communicative, environmental, somatic (dental pain, reflux, constipation, decompensation of epilepsy) or psychiatric (anxiety, depression) causes, or a lack of enjoyable activities, giving priority to the search for pain; educational, behavioural and environmental measures are always the first approach, sensory enrichment should be structured so as not to reinforce repetitive behaviours, and antipsychotics are used with great caution, at low dose and with monitoring for sedation and extrapyramidal effects, antidepressants being better-tolerated alternatives depending on the symptoms [34].

The weight curve and BMI are monitored regularly: dietetic follow-up with assessment of eating behaviour in the event of a change in percentile or overweight (BMI above the 97th percentile in children or above 25 kg/m² in adults) and specialist endocrinology and nutrition assessment if BMI exceeds the IOTF 30 threshold in children or 30 kg/m² in adults, with investigation of familial and drug-related factors, body composition and metabolic and respiratory comorbidities. Control of access to food, structured and predictable meals, refusal to use food as a reward or punishment and physical activity at least two to three times a week complete the approach, and the PNDS refers to the generic PNDS on obesity of rare causes. In early childhood, speech and language therapy targeting oral motor function and positioning at mealtimes (sometimes with a seating shell) improve feeding, saliva swallowing and nasal breathing, and diversification of textures is recommended to avoid food selectivity [34].

For communication, the PNDS applies the principles used in severe disability: the right to communication, involvement of communication partners and early and sustained introduction of robust augmentative and alternative communication (broad vocabulary, combination of symbols and the possibility of expressing all communicative acts), without prerequisites, starting at diagnosis or, at any age, as soon as the absence of a robust system is noted. Pointing and symbol identification develop through use modelled by communication partners, enhanced natural gesture builds on action gestures already mastered, and supports such as visual schedules, life books, aided language boards and the communication passport extend communication across settings. Assessment serves to adjust the intervention (pragmatic profile, Communication Matrix, structured observation), and coaching of caregivers is indispensable, given the frequent abandonment of systems during the pre-symbolic phase [34].

For motor function, early physiotherapy is recommended, without evidence to support prolonged intensive programmes, together with standing for non-ambulant patients (intestinal transit and bone mineralisation), psychomotor therapy, occupational therapy for independence in daily activities and regular physical activity in line with recommendations for multiple disabilities: two to three weekly sessions of aerobic training, muscle strengthening and coordination and balance. The spine is monitored clinically, with radiography whenever there is doubt and systematically at puberty; bracing slows progression and, in ambulant children, a night-time overcorrection brace avoids immobilising the child during the day. Posterior spinal fusion is indicated for severe curves (above 45°), with decreasing reducibility, progression, neurological risk or respiratory impact, is timed according to the end of trunk growth and follows respiratory and cardiac assessment, and improves pain, respiratory function and participation, but not motor capacity. Botulinum toxin can treat spastic equinus and knee flexion deformity, with the indications used in cerebral palsy, and postoperative complications (wound healing, infection, bone union) are known and preventable [34].

Data on anaesthesia are scarce: one case of bradyarrhythmia, possibly vagal, under sevoflurane and nitrous oxide, and reports of bronchospasm, increased sensitivity to benzodiazepines and difficult extubation, which the authors relate to modulation of GABA-A receptors, whose genes are included in the deletions [34]. For dental care, the PNDS recommends an annual examination even without complaints, with interproximal (bitewing) radiographs, fluoride prevention and oral assessment before bone antiresorptive agents; care is attempted first while awake (possibly with hypnosis), then with sedative premedication (hydroxyzine, midazolam or diazepam, with monitoring of vital signs), with conscious sedation using an equimolar mixture of oxygen and nitrous oxide (EMONO), unless contraindicated (need for pure oxygen, intracranial hypertension, impaired consciousness, pneumothorax, bullous emphysema, gas embolism, diving accident, gaseous abdominal distension, facial trauma in the mask area), and, as a last resort, under general anaesthesia; glass ionomers and stainless steel crowns better withstand bruxism, and maxillary splints have unpredictable tolerance [34]. Therapeutic education covers adapted physical activity, body and oral hygiene, safety and rescue treatment for seizures and, where applicable, enteral nutrition by tube or gastrostomy [34].

7.2 Investigational therapies in Angelman syndrome

Several pharmacological approaches have failed. Oral supplementation with folate, vitamin B12, creatine and betaine, intended to increase methylation and paternal allele expression, showed no significant clinical benefit [1, 75]. Gaboxadol (OV101), a selective agonist of extrasynaptic GABA-A receptors, was well tolerated in the phase 2 STARS trial, whose primary objective was safety, and an exploratory analysis suggested improvement in clinical global impression with the single nightly dose; the phase 3 NEPTUNE trial, in children aged 4 to 12 years, showed no difference from placebo on the primary endpoint, and development for this indication was not pursued [76, 77]. Levodopa/carbidopa had no significant benefit in a randomised trial [78]. This trial was preceded by an open-label phase 1-2 study in six children, designed to define the maximum tolerated dose, and NNZ-2591, a cyclic dipeptide analogue with neuroprotective action, was evaluated orally in an open-label safety and pharmacokinetic study in Australia (NCT05011851, phase 2, 17 participants, completed in July 2024, with no results in the registry) [34, 79]. Minocycline was tested in an open-label pilot trial in children, but the randomised, double-blind, crossover A-MANECE trial, in 32 Spanish patients aged 6 to 30 years, showed no benefit over placebo in the change in the developmental index of the revised Merrill-Palmer scale after 8 weeks (1.90 vs. 2.00; p = 0.937), nor with 16 weeks of treatment [80]; ketone ester supplementation attenuated seizure activity in a mouse model, without established clinical translation [81, 82]. Magnesium, suggested for the BP1-BP2 microdeletion and for a subgroup of patients with AS or PWS with a class I deletion, has not been evaluated in controlled trials [23].

The most advanced strategy is reactivation of the paternal UBE3A allele with intrathecally administered ASOs that inhibit the UBE3A-ATS transcript [24, 25]. Table 7 summarises the status of the three molecules in October 2026.

Data from [24–27, 83–87]. Apazunersen held Breakthrough Therapy, orphan drug and Fast Track designations from the FDA and orphan and PRIME designations from the EMA [85]. The negative result of Aspire, the first phase 3 trial of an ASO in AS to be completed, introduces uncertainty about the clinical translation of UBE3A reactivation and about the sensitivity of endpoints based on the Bayley-4; Samanta's 2026 review identifies the limitations of outcome measures, genotype stratification, long-term safety and equity of access as challenges [25, 85]. Gene replacement with the viral vector MVX-220 has entered a phase 1/2 trial (NCT07181837; 4 to 50 years, about 12 participants, recruiting since October 2025, primary safety endpoint), and alogabat (RO7017773), a GABA-A receptor modulator, was evaluated in a phase 2 study in children and adolescents aged 5 to 17 years (NCT05630066; completed in December 2025, with a pharmacodynamic endpoint of EEG beta power), with no published results identified [88, 89]. In the original design of the phase 1/2 apazunersen trial, the first five patients, treated with the highest doses (36 mg in four and 20 mg in one), developed inflammatory lower-limb weakness, which resolved within weeks with corticosteroids and immunoglobulins; the protocol was amended, with individual titration over three to four monthly injections and quarterly maintenance up to 14 mg [34]. CRISPR activation, epigenetic editing, artificial transcription factors and delivery platforms that cross the blood-brain barrier are in preclinical or early development [25]. Families can be directed to registries such as LADDER (Linking Angelman and Dup15q Data for Expanded Research) [2].

7.3 Maternal 15q duplication syndrome

Multidisciplinary assessment of motor and speech development is recommended from early childhood, followed later by referral to appropriate educational programmes [2]. Initial assessment includes growth parameters and oral feeding safety, neurological assessment (EEG if seizures are suspected), assessment of motor function and activities of daily living, developmental assessment and, from 12 months, screening for sleep disturbance, ADHD, anxiety and ASD [2]. Treatment includes feeding therapy (gastrostomy for persistent difficulties, with a radiological swallowing study when there are signs of dysphagia), physiotherapy, occupational therapy, augmentative and alternative communication (which supports rather than delays speech), ABA and psychotropic drugs for behavioural manifestations [2].

Epilepsy is treated with antiseizure medication, vagus nerve stimulation or a ketogenic diet; there are no prospective or randomised data in dup15q. In a survey of 95 families, broad-spectrum drugs were the most effective, carbamazepine and oxcarbazepine were also effective, typical benzodiazepines were relatively ineffective and, for infantile spasms, adrenocorticotropic hormone (ACTH) was more effective than vigabatrin; only 24% responded (> 90% reduction) to the first drug [2, 54]. Neurostimulation has promising results in small series [90]. Soticlestat, a cholesterol 24-hydroxylase inhibitor, was evaluated in an open-label phase 2 study (ARCADE) and was associated, in dup15q (n = 8), with a median 11.7% increase in motor seizure frequency, despite a 23.4% reduction in total seizures, so there is no support for its use in this syndrome [91]. Basmisanil, a negative allosteric modulator of the α5-containing GABA-A receptor, was studied in a phase 2 trial in children aged 2 to 14 years, terminated by sponsor decision unrelated to safety, and a new phase 2 trial, with a primary endpoint of quantitative EEG beta power, was planned for December 2026 [92].

The French PNDS for dup15q defines the initial assessment: a genetics clinic consultation with growth parameters and dysmorphology, cytogenetic testing of both parents and counselling; paediatric neurology assessment, with brain MRI only in the presence of macrocephaly, epilepsy or motor or behavioural regression, and EEG when there are signs suggestive of seizures (falls, repeated night-time awakenings, unexplained episodes); psychiatric (social anxiety, ADHD, ASD, challenging behaviour), neuropsychological and social cognition assessment; ophthalmological assessment, ENT assessment with an audiogram, gastroenterological assessment in the presence of constipation or feeding difficulties and endocrinological assessment for unexplained short stature, to exclude growth hormone deficiency; and assessments by speech and language therapy oriented towards augmentative communication, orthoptics and occupational therapy, with referral, if useful, to a reference centre for learning and language disorders. Diagnosis of ASD requires the ADOS-2 and ADI-R complemented by clinical observation, because language delay, the possibility of selective mutism and anxiety can lead to both underdiagnosis and overdiagnosis, and referral to an autism resource centre is indispensable [46].

For treatment, the PNDS neither recommends nor contraindicates any antiseizure medication a priori: broad-spectrum drugs are used, as in severe generalised epilepsies and Lennox-Gastaut syndrome, introduced sequentially and withdrawn if ineffective or poorly tolerated, but benzodiazepines and other GABAergic drugs are not first-line, because of the poor efficacy and potential worsening of seizures reported by families. Methylphenidate is considered for ADHD confirmed by neuropsychological assessment, after checking the SmPC contraindications (doses in Table 7D), and combinations of psychotropic drugs require interactions to be excluded. It further recommends swallowing and orofacial rehabilitation, enteral nutrition by tube or gastrostomy for severe feeding disorders, with parent education, standard treatment of GORD, early treatment of constipation before encopresis sets in, assessment of the sensory profile (auditory filters, accepted textures, weighted blankets), investigation for otitis media with effusion before language assessment, with tympanostomy tubes if necessary, systematic oral follow-up with fluoride varnish and care under EMONO or within a specialised oral health network when necessary, and, in the event of a sudden change in behaviour, a search for pain with adapted scales (Pédiadol, San Salvadour) or for depression or anxiety after a significant event. Therapeutic education addresses the management of treatments, what to do during a seizure and the transition to adulthood [46].

SUDEP prevention relies on the best possible seizure control; approximately half of epilepsy-related deaths are due to status epilepticus, drowning, falls and accidents, some of which are preventable, and rescue medication (rectal diazepam, intranasal midazolam) prevents status epilepticus; detection devices (wrist and mattress accelerometers) may detect events but do not prevent SUDEP [2]. Seizure triggers such as sleep deprivation, stress and non-adherence to treatment should be avoided [2].

7.4 15q11.2 BP1-BP2 microdeletion

There is no specific treatment. Management comprises assessment of development and learning, speech and language therapy and educational intervention, behavioural and psychiatric assessment (ADHD, ASD, anxiety, psychosis), and treatment of epilepsy when present [5, 23]. Magnesium supplementation, proposed on the basis of parental observations and the transporter function of NIPA1 and NIPA2, lacks controlled studies and should not be presented as an established treatment [23]. The development of late neuropsychiatric symptoms warrants prolonged follow-up and multidisciplinary care [93].

7.5 Clinical trials: results and limitations of comparison

Table 7B summarises therapeutic trials with available results in AS and dup15q, including negative trials.

These trials do not allow interventions to be ranked. Primary endpoints differ (safety, adapted clinical global impression scales, Bayley raw scores, composite indices), populations differ in age and genotype (Aspire included only deletions, and CHAMPION will include only UPD and imprinting defects), and favourable signals derive from exploratory analyses, uncontrolled open-label studies or comparisons with natural history data, which do not replace a randomised control group. The STARS–NEPTUNE sequence, in which an exploratory phase 2 signal was not confirmed in phase 3, and the negative Aspire result after phase 1/2 signals illustrate the risk of overinterpreting early results; negative trials should be presented to families with the same prominence as positive trials. Absence of a difference in a 12-week or 11-month endpoint also does not demonstrate absence of a longer-term effect, but does not authorise use outside a trial.

7.6 Regulatory status, hierarchy of evidence and off-label use

In October 2026, neither the United States nor the European Union has any medicine authorised for AS, dup15q or the BP1-BP2 microdeletion as diseases; the drugs used are authorised for seizure types, epilepsy syndromes or sleep disorders, and their use in these syndromes rests on extrapolation of evidence obtained in other populations [1, 25]. Table 7C compares the regulatory status of the drugs cited in this article.

Data from [1, 66, 67, 85, 94].

Four levels of evidence are distinguished when interpreting new developments: peer-reviewed publication (phase 1 TANGELO, NEPTUNE, the Munich cohort), sponsor announcements or regulatory documents (the Aspire result, completion of REVEAL recruitment, initiation of BEACON), the trial registry (status, population and endpoints), and the regulatory decision, which does not exist for any of these molecules. Orphan drug, PRIME or breakthrough therapy designations are development incentives and do not equate to authorisation; a future authorisation would also not guarantee reimbursement or access in Portugal or Brazil, which depend on national assessment (INFARMED; ANVISA and CONITEC).

Extrapolation of evidence should be distinguished from off-label use. Extrapolation consists of applying to AS data obtained in other populations, such as levetiracetam trials in focal and generalised epilepsies, clobazam trials in Lennox-Gastaut syndrome or melatonin trials in ASD; off-label use depends on the label wording, age and jurisdiction. Levetiracetam in a 4-year-old child with focal seizures is within the indication in both jurisdictions, although the evidence in AS is extrapolated; clobazam in a child with AS without Lennox-Gastaut syndrome is outside the US indication; nasal diazepam before 2 years and nasal midazolam before 12 years are outside the US label; and melatonin in an adult with AS is outside the Slenyto® indication. Pregnancy in women with AS is exceptional, but any prescription in this context requires checking each drug's SmPC.

7.7 Divergences between the French PNDS documents and the other sources

Table 7E compares the recommendations and data of the two HAS PNDS documents with the other sources cited; for doses, the reference is the guideline dose and the label serves as a comparison.

8. Reproductive Options and Family Counselling

8.1 Angelman syndrome: recurrence risk by molecular class

Reliable assessment of recurrence risk requires identification of the mechanism in the proband and confirmation of the parents' genetic status [1, 12]. Table 8 summarises the recommendations.

Adapted from [1, 12, 32]. OXF estimates the risk after UPD at less than 1/200 and recommends exclusion of a parental Robertsonian translocation [12]. In class Ia, maternal germline mosaicism has been documented in families from Finland, Spain and China [12, 35, 36]. In class IV, a mother who tests negative still has a significant risk of gonadal mosaicism, so prenatal diagnosis should be offered [12, 40]. Imprinting defects without IC deletion are usually sporadic and frequently mosaic, with a low recurrence risk [12]. Genomic inversions of 15q11-q13 in mothers of children with BP2-BP3 deletions, inverted intrachromosomal insertions and inversions disrupting UBE3A (described in Japanese siblings) justify cytogenetic investigation of the mother [1, 95]. In general, purely epigenetic errors are reprogrammed in the next generation and UPD is a reproductive error with a recurrence risk close to that of the population, whereas coding variants and copy number changes can be inherited, with expression dependent on the sex of the transmitting parent [14]. A rare exception was published in 2026: a neurotypical father with a small mosaic supernumerary marker chromosome 15, with three cell lines (one of them with a deletion including SNRPN), transmitted AS to several children; UPD was excluded, and the authors propose that the mitotically unstable marker compensated for the deletion in the father and interfered with imprint resetting in the germline [96]. The case reinforces the need for cytogenetic characterisation of both parents when transmission does not follow the expected pattern. The French PNDS groups the situations into low recurrence risk (deletion, paternal UPD and de novo UBE3A variant) and high risk, up to 50% (deletion inherited from a balanced maternal rearrangement or a paternal Robertsonian translocation involving chromosome 15, inherited UBE3A variant, inherited imprinting defect and, subject to the clinical diagnosis, absence of a molecular alteration), recommends in all cases a dedicated counselling consultation with a family history enquiry and stresses that, in class V, there are familial recurrences of unquantifiable risk and prenatal diagnosis is not possible [34].

8.2 At-risk relatives and offspring

When the mother carries a UBE3A variant, an IC deletion or a structural rearrangement (or the father, in UPD with a Robertsonian translocation), their siblings should receive genetic counselling and the option of testing [1, 12]. Each child of an unaffected carrier sister has a 50% risk of AS; carrier maternal uncles do not have affected children but may have affected grandchildren through daughters to whom they transmit the alteration [1]. A woman carrying a UBE3A variant has a 50% risk of AS in each pregnancy, whereas a male carrier transmits the variant without a clinical effect in his children, because the paternal allele is silenced [12]. To date, only one person with AS has had documented offspring, a woman with a 15q11.2-q13 deletion who transmitted it to the fetus; the risk to offspring should be determined through formal counselling [1].

8.3 Prenatal and preimplantation diagnosis

Prenatal diagnosis of all known classes (Ia to IV) is possible through DNA and/or chromosomal analysis and FISH in chorionic villi or amniocytes, but should be performed only after the mechanism in the proband has been established and the risk discussed with the couple [1]. If the cytogenetic basis was defined by FISH, this is the method of choice; if a UBE3A variant, deletion or IC deletion is known, diagnosis in chorionic villi is possible [12]. Methylation analysis is theoretically possible in villi, but laboratories prefer amniocytes because of relative hypomethylation of placental cells; in a small study, SNRPN methylation gave correct diagnoses in 24/24 amniocentesis and chorionic villus samples, although caution is advised because of theoretical imprinting instability in the trophoblast, and an experienced laboratory should be used [1, 12]. Parents with normal chromosomes and a child with a deletion or UPD have a low risk but may choose prenatal diagnosis for reassurance; parents of a child with a UBE3A variant should be counselled to undergo prenatal diagnosis even if the mother tests negative [1]. Preimplantation genetic testing (PGT) is an option when the mechanism is a UBE3A variant or an IC deletion; early embryonic hypomethylation makes PGT unsuitable for methylation testing [1].

In low-risk pregnancies, AS should be considered if a 15q11.2-q13 deletion is suspected in chorionic villi or amniocytes (confirmation by FISH or CMA and parent-of-origin studies to distinguish AS from PWS); if trisomy 15 or mosaic trisomy 15 is detected in chorionic villi and amniocentesis shows 46 chromosomes (risk of trisomy rescue with paternal or maternal UPD); or if a de novo translocation involving chromosome 15 or a supernumerary marker of chromosome 15 is detected [1]. OXF recommends amniocentesis after detection of trisomy 15, mosaic or not, in chorionic villi, because in the EUCROMIC study the trisomic line originated from a meiotic error in about 50% of cases of trisomy 15 confined to the placenta, with a risk of UPD (paternal, AS; maternal, PWS) and of true fetal mosaicism [14]. In carriers of balanced Robertsonian translocations, a review of 315 prenatal diagnoses found UPD in two cases (estimated risk 0.65%), and in a series of 174 acrocentric rearrangements detected prenatally, UPD occurred in 1/168 (0.6%) non-homologous translocations and in 4/6 homologous rearrangements; OXF recommends considering UPD testing for any rearrangement involving chromosome 14 or 15 [14]. In vitro fertilisation and intracytoplasmic sperm injection increase the risk of some imprinting disorders, such as Beckwith-Wiedemann syndrome; one study detected one case of AS due to an imprinting error among 949 pregnancies after in vitro fertilisation, and other studies have not shown a significant association; families from the Netherlands and Germany reported previous fertility problems in 19-25% of couples with a child with AS, an association not confirmed in the United Kingdom [1, 97, 98]. The PNDS mentions cases of AS due to an imprinting defect after medically assisted reproduction, without establishing causality, and provides for prenatal diagnosis, discussed case by case, only when the alteration has been identified in the proband [34].

8.4 Maternal 15q duplication syndrome

Maternal dup15q is an autosomal dominant condition, usually de novo [2]. All cases of idic(15) with parents tested have been de novo, and the risk to siblings is low, although slightly higher than that of the population owing to the theoretical possibility of maternal germline mosaicism; a single maternal transmission of a supernumerary partial trisomy of the region has been described, in a family in which the child had intractable epilepsy and the mother schizophrenia [2, 99]. People with idic(15) have no known offspring [2]. In interstitial duplication, about 85% are de novo and 15% are inherited from the mother; if the mother is a carrier, the risk to each child is 50%, with no possibility of predicting severity [2]. A mother who inherited the duplication from her father may be asymptomatic or have the paternal duplication phenotype; a female carrier transmits the maternal form, whereas a male carrier transmits the paternal form, of more variable expression [2]. Prenatal diagnosis and PGT by CMA are possible but do not predict severity [2]. For supernumerary markers in general, de novo markers have a very low recurrence risk and familial markers have a high transmission risk; when a parent is a mosaic carrier, the child may inherit the marker in mosaic or non-mosaic form, with wide phenotypic variability [44]. In prenatal diagnosis, about 50% of supernumerary markers derive from chromosome 15: if FISH shows a marker dicentric for the chromosome 15-specific alpha-satellite sequence and with two copies of the PWACR (which can also be defined by CMA), the prognosis is invariably poor, with severe developmental delay, autistic features, behavioural problems and epileptic seizures; a dicentric chromosome 15 marker without PWACR euchromatin is associated with normal development, provided that UPD 15 is excluded when the marker is de novo [44]. Transmission of a chromosome 15-derived marker by a mosaic parent to a non-mosaic child is extremely rare but may increase the risk of abnormality or of UPD 15 [44]. According to the French PNDS, the mother is a carrier in about 15% of interstitial duplications, with a 50% risk in each pregnancy and an indication to discuss prenatal and preimplantation diagnosis; for a de novo duplication, the recurrence risk is about 1%, above that of the population owing to germline mosaicism, which justifies offering prenatal diagnosis by CMA or FISH on chorionic villi or amniocytes, and the genetics clinic consultation should be brought forward if another pregnancy is under way. Prenatally, severity cannot be predicted, although copy number appears to correlate with it; in France, a request for termination of pregnancy for medical reasons is reviewed by a multidisciplinary prenatal diagnosis centre and is usually accepted, and prenatal disclosure includes the features of the condition, the follow-up options, the possibility of other specialist opinions, genetic counselling and contact with support associations, whether the pregnancy is terminated or continued [46].

8.5 15q11.2 BP1-BP2 microdeletion

The deletion is inherited in most cases (0/27 de novo in Rosenfeld's series), frequently from a parent without a phenotype, and each child of a carrier has a 50% risk of inheriting it [8, 57]. For an apparently isolated de novo CNV, the recurrence risk is low (approximately 1%), attributable to parental mosaicism [57]. Prenatal counselling should reflect low penetrance: in a Chinese cohort of 5,246 high-risk pregnancies, 25 fetuses had the deletion, and none of the 20 liveborn children followed between 3 months and 3 years and 8 months showed developmental or growth abnormalities; in the literature review, penetrance in cases with standardised paediatric follow-up was 5.5% [59]. There is no consensus on cascade screening or prenatal diagnosis of susceptibility CNVs because of prognostic uncertainty [28, 57].

9. Special Considerations: Population Diversity and Epidemiology

The population prevalence of AS is estimated at 1:12,000 to 1:24,000 [1], and the textbook sources cite 1:25,000 (OXF), 1:12,000 to 1:20,000 (Smith) and 1:15,000 (SGRT) [10, 12, 33]; Samanta's 2026 review reports about 1:15,000 live births [25]. The French PNDS estimates the prevalence at between 1/10,000 and 1/20,000 and considers AS probably underdiagnosed [34]. The only national birth incidence study with genetic confirmation, from Denmark, identified 51 patients and an incidence of 1:24,580 (95% CI 1:23,727-1:25,433), with 36 deletions (13 class I and 20 class II, and three larger atypical deletions), five paternal UPDs and four UBE3A variants [6]. Orphanet records a worldwide point prevalence of 7.5/100,000 and birth prevalences of 1.3/100,000 in Europe (EUROCAT), 2.5/100,000 in Australia, 5.0/100,000 in Spain (point prevalence 8.3/100,000) and 1.8/100,000 in Estonia, as well as a point prevalence of 4.0/100,000 in the United Kingdom [3]. These differences mainly reflect ascertainment methods and underdiagnosis rather than known biological differences. AS occurs with equal frequency in both sexes and no founder effects have been described [1].

No population studies of AS prevalence in Latin America, Africa, the Middle East or mainland Asia were identified in the sources consulted, which does not demonstrate their non-existence; available data derive from clinical series and case reports describing molecular class distribution and phenotype, but do not measure prevalence. The most extensive clinical data come from European cohorts (Denmark, the Netherlands and Munich) and North American cohorts (surveys and the LADDER registry), describing referred patients rather than the general population [2, 6, 43, 51, 68]. In Brazil, Koiffmann and colleagues' group in São Paulo published one of the first reports with cytogenetic and molecular confirmation of a maternal deletion and studied the origin of UPD 15 in a series of patients with PWS and AS, showing that paternal UPD in AS is predominantly postzygotic in origin [37, 100]. Maternal germline mosaicism for a 15q11-q13 deletion and prenatal cohorts of the BP1-BP2 microdeletion have been described in Chinese populations [36, 59]. Ethnic diversity modifies the expression of hypopigmentation: because pigmentation depends on the family's genetic background, assessment should compare the patient with relatives, and in African and African-descended populations, in which oculocutaneous albinism type 2 is frequent, coexistence of an OCA2 variant on the non-deleted chromosome may produce oculocutaneous albinism associated with AS [1, 30].

In dup15q, idic(15) has an estimated birth incidence of 1:30,000 (3.33/100,000) and an unknown point prevalence according to Orphanet [4, 19]; the French PNDS adopts a prevalence of about 1/30,000 births, equal in both sexes [46]; maternal dup15q is found in about 1:522 people with ASD, making it one of the most frequent cytogenetic abnormalities in this population [2, 7]. The Dup15q Alliance registry included about 709 families in 2012 [56]. In South America, reports are scarce: the first published Ecuadorian patient had an atypical de novo maternal interstitial duplication, between BP1 and a breakpoint within SNHG14, not covering the whole PWACR, with a phenotype resembling mild PWS, and the authors estimated the worldwide frequency of dup15q at between 1:30,000 and 1:60,000 children [101]. For the BP1-BP2 microdeletion, the frequency in referred populations is 0.57-1.27% and in controls 0.38%, making it one of the most frequent pathogenic CNVs on CMA; Orphanet does not assign a point prevalence [4, 5, 8]. In the sources consulted, no region-specific prevalence data were identified for dup15q or for the BP1-BP2 microdeletion outside European, North American and Chinese cohorts.

10. Illustrative Clinical Case

10.1 Classic Angelman syndrome due to maternal deletion (Brazilian report)

In 1997 in São Paulo, Fridman and colleagues described a patient with typical AS: developmental delay, intellectual disability, macrostomia, widely spaced teeth, epileptic seizures, absent speech, a gait with jerky movements and paroxysms of laughter; cytogenetic and molecular studies demonstrated a maternal 15q11q13 deletion, consistent with the clinical diagnosis [100]. The report, whose title describes a frequently undiagnosed cause of intellectual disability and epilepsy, illustrates the importance of recognising the behavioural and electroencephalographic phenotype. In counselling this family, because this is a class Ia deletion with a normal maternal karyotype, recurrence risk is below 1%, with the caveat of maternal germline mosaicism, and prenatal diagnosis may be offered for reassurance [1, 12].

10.2 Mosaic Angelman syndrome due to an imprinting defect

Fairbrother and colleagues reported a girl with AS due to a mosaic imprinting defect, with relatively high adaptive function (Vineland-II composite score of 76) and expressive communication skills documented on video, without seizures, gait abnormalities or inappropriate laughter [53]. AS was not initially suspected; initial tests were inconclusive, and additional studies suggested a mosaic imprinting defect, supported by characteristic electroencephalographic findings [53]. The authors raise the possibility of an undiagnosed group of people with mild intellectual disability and expressive language delay due to mosaic methylation defects at 15q11.2-q13 [53]. The case demonstrates that SNRPN methylation should be considered in a broader clinical context and that recurrence risk in imprinting defects without IC deletion is low [1, 39].

10.3 Familial maternal partial trisomy 15q11-q13

Michelson and colleagues described a 10-year-old girl with normal intelligence until severe, intractable epilepsy began at seven years; her mother had recurrent episodes of acute psychosis [99]. Both had a 47,XX,+mar karyotype, and array comparative genomic hybridisation identified a gain from 15q11.2 to 15q13.1, which FISH confirmed was part of the marker and included the SNRPN/UBE3A locus [99]. The case, the only record of maternal transmission of supernumerary partial trisomy of this region cited by GeneReviews, shows that the same duplication can manifest as intractable epilepsy in the child and psychiatric disease in the mother, with preserved intelligence, and supports the recommendation for CMA in intractable epilepsy and schizophrenia [2, 99].

10.4 15q11.2 BP1-BP2 microdeletion with late-onset psychosis

Das and colleagues reported a 51-year-old Caucasian woman diagnosed with Burnside-Butler syndrome at eight years who developed late-onset psychotic symptoms, and reviewed the syndrome's neuropsychiatric spectrum (psychosis, aggression, mood and anxiety disorders, learning difficulties, language delay, ASD and ADHD) [93]. The case emphasises the need for lifelong psychiatric surveillance and multidisciplinary care, but should be interpreted in light of population data attributing a mild effect and an absolute schizophrenia risk of approximately 2% to the deletion [28, 93]. The full report is available in open access (https://pmc.ncbi.nlm.nih.gov/articles/PMC10826381/).

10.5 Atypical maternal interstitial duplication without UBE3A (Ecuadorian report)

Ortiz-Prado and colleagues described an Ecuadorian boy, the second child of healthy, non-consanguineous 35-year-old parents, born at 38.5 weeks by induced vaginal delivery, weighing 2,575 g with an Apgar score of 8/9 [101]. After feeding vigorously at the breast in the first hours, he developed acute, severe hypotonia, unresponsiveness, somnolence, absent tendon reflexes, a Babinski sign and shallow breathing, prompting admission to neonatal intensive care; infectious, metabolic and neurological investigations were negative, brain MRI was normal (figure 1 in the original article) and the karyotype was 46,XY (figure 2) [101]. MS-MLPA showed an abnormal SNRPN methylation pattern attributed to a maternally derived interstitial 15q11-q13 duplication of at least 2.4 Mb (figure 3), and array comparative genomic hybridisation defined arr[GRCh37] 15q11.2(22765637_25259734)x3 (figure 4), with TUBGCP5, CYFIP1, NIPA1, NIPA2, MKRN3, MAGEL2, NDN, SNURF-SNRPN and SNHG14 among the duplicated genes; the distal breakpoint lay within SNHG14, and the list of duplicated genes does not include UBE3A, although the authors' text states that the duplication encompasses the entire PWACR [101]. At 36 months, the child had mild motor delay (head control at 6 months, supported sitting at 9, wide-based walking at 20), generalised hypotonia, short stature (−2.18 SD), central obesity, almond-shaped eyes, narrow hands and feet, a small penis, surgically treated bilateral cryptorchidism and hyperphagia, without ASD or epilepsy, with normal EEG and MRI and a Mullen early learning composite score of 63 [101]. The figures can be viewed in the original open-access article (https://pmc.ncbi.nlm.nih.gov/articles/PMC8110389/). The case shows that a maternal duplication of the region not including UBE3A may differ from the dup15q phenotype and resemble mild PWS, consistent with the central role of increased UBE3A dosage in dup15q, and that an abnormal MS-MLPA methylation pattern should be interpreted together with dosage before concluding PWS or AS [2, 101]; it is, however, an isolated report.

11. Prognosis and Long-Term Follow-up

11.1 Angelman syndrome

Intellectual disability is severe and non-progressive [10]. Young adults are generally in good physical health, and the risk of other diseases appears similar to that of the general population; life expectancy approaches normal in the absence of serious complications such as severe scoliosis or difficult-to-control epilepsy, and some people have lived into their 60s and 70s [1, 10, 12, 52]. Independent living is not possible: most live at home or in family-type residences and require continuous supervision, while being able to enjoy a good quality of life [1, 12]. Most achieve daytime continence and some also night-time continence [10]. In adolescence and adulthood, seizures (with NCSE), loss of mobility and joint contractures, scoliosis, reflux, constipation, sleep disturbances, hyperphagia and obesity, and low bone mineral density with reports of an increased fracture risk persist, and a series of 53 adolescents and adults documented these complications and the need for an organised transition to adult care [12, 52, 102]. The French PNDS considers life expectancy poorly known and probably slightly reduced, with possibly bimodal mortality (early deaths from severe epilepsy or accidents, favoured by curiosity, hyperactivity and the lack of awareness of danger), describes patients in their seventh decade and stresses that learning continues into adulthood. In France, the transition is often marked by disruption, with continued placement in a medico-educational institute beyond 20 years of age under the “Creton” provision and a search for a place in a medicalised residential home or specialised residential home; the PNDS recommends preparing in advance the updating of assessments and a clinical transition process [34]. Challenging behaviours in adolescence and adulthood include communicative frustration, seeking of sensory stimulation and social attention, and avoidance of unwanted situations [1].

Adapted from [1, 34]. The PNDS intervals result from expert consensus; GeneReviews does not set frequencies for most systems, which makes the French framework the only published reference for visit frequency.

11.2 Maternal 15q duplication syndrome

Prognosis depends predominantly on the mechanism and epilepsy: idic(15) is associated with more severe disability and refractory epilepsy, and children with epilepsy have lower cognitive and adaptive function than those without epilepsy [2, 55]. In a mortality study from the Dup15q Alliance registry, 19 deaths occurred in people with idic(15), 17 of whom had epilepsy; nine were probable or definite SUDEP (median age 13.5 years, range 3-26) and two possible SUDEP, and the remainder were due to status epilepticus (3), pneumonia (3), aspiration (1) and drowning (1) [56]. SUDEP occurs in approximately 9% of people with epilepsy in general, but its specific incidence in dup15q is unknown [2]. Follow-up includes, at every visit, growth and feeding safety, monitoring of seizures and changes in seizure type, development and educational needs, anxiety, attention and aggressive or self-injurious behaviour, mobility and needs for social support, palliative or respite care and home nursing; siblings of probands with an inherited interstitial duplication should be tested to enable early intervention [2].

Table 11B summarises the follow-up proposed by the French PNDS for dup15q.

At the transition to adulthood, the PNDS recommends a genetics clinic consultation and a transition consultation to maintain psychiatric, neurological and rehabilitation follow-up and avoid loss of acquired skills; vocational guidance, place of residence and adult protection are decided at this stage. The French framework does not include surveillance directed at SUDEP, which GeneReviews addresses [2, 46].

11.3 15q11.2 BP1-BP2 microdeletion

Most carriers identified prenatally or through family testing have normal development or mild abnormalities, and the mean effect on IQ is approximately 4 points [28, 59]. In symptomatic carriers, follow-up focuses on learning, language and behavioural difficulties and surveillance for epilepsy and psychiatric disease, including psychosis, which may develop in adulthood [5, 93].

11.4 Reference networks and patient associations

In Europe, the relevant European Reference Network for all three entities is ERN ITHACA, dedicated to rare malformation syndromes and rare intellectual and developmental disabilities, and ERN EpiCARE covers rare and complex epilepsies, relevant to AS and dup15q with refractory epilepsy [103, 104]. Patient associations and foundations include the Angelman Syndrome Foundation (United States), the Foundation for Angelman Syndrome Therapeutics (FAST), the Angelman Syndrome Alliance, an international federation of national associations, the Dup15q Alliance, responsible with other organisations for the LADDER registry, and Unique, supporting people with rare chromosomal abnormalities, including 15q11.2 deletions and duplications [1, 2, 105–107].

In France, AS is managed by the reference centre “Déficiences intellectuelles de causes rares” (coordinated at the Pitié-Salpêtrière in Paris, with constituent centres in Lyon, Marseille, Paris, Dijon, Brest, Rennes and Strasbourg and competence centres in other cities), part of the DéfiScience network, and dup15q by the “Anomalies du développement et syndromes malformatifs” reference centres of the AnDDI-Rares network (the PNDS was coordinated by the Marseille centre), in liaison with the DéfiScience centres and, for severe epilepsy, with the rare epilepsy centres. Full (100%) coverage is obtained by applying for exemption from the ticket modérateur as an off-list condition; benefits include the AEEH, the PCH, the mobility-inclusion card, the AJPP and, in adults, the AAH and legal protection measures, and in idic(15) an 80% disability rate may be granted under the derogation for numerical chromosomal abnormalities. Both PNDS documents provide for an emergency card based on the national rare disease model: the AS card records the associated disorders (epilepsy, sleep, vision, hearing, balance, reflux, constipation, aspiration, ingestion of small objects), current treatment, means of communication and an alert about the difficulty in expressing pain; the idic(15) card highlights as first-priority emergency information epilepsy, GORD, recurrent pulmonary infections, behavioural disorders and ASD, and the high pain threshold. The French associations are the Association Française du Syndrome d'Angelman (AFSA), which took part in drafting the PNDS, Syndrome Angelman-France, Valentin APAC, Association dup 15q and L'Everest d'Ernest [34, 46].

12. Summary and Final Considerations

The 15q11-q13 region brings together, within a segment of a few megabases bounded by BP1 to BP5 repeats, a bipartite imprinting centre, exclusively paternally expressed genes, UBE3A, which is maternally expressed in neurones, and a cluster of GABA-A receptor genes. Rearrangements mediated by these repeats give rise, according to the type of alteration and parental origin, to AS (loss of the maternal UBE3A contribution), PWS (loss of the paternal contribution), maternal dup15q (gain of maternal PWACR copies) and the BP1-BP2 microdeletion, which removes four non-imprinted genes and acts as a susceptibility factor of mild effect [1, 2, 22, 28].

In AS, diagnosis rests on the clinical consensus criteria and on the algorithm that begins with methylation analysis (about 80% of cases) and continues with UBE3A sequencing (about 11%); distinguishing between deletion, paternal UPD, imprinting defect with or without IC deletion and UBE3A variant is essential, because the recurrence risk ranges from less than 1% to 50% and, exceptionally, close to 100% [1, 12, 18]. Mosaic forms due to an imprinting defect have a milder phenotype, with expressive language and hyperphagia, and may be confused with PWS or non-specific intellectual disability [39, 53]. Treatment remains symptomatic, focused on epilepsy, sleep, augmentative communication and the avoidance of overtreatment; among the ASO therapies that reactivate the paternal allele, apazunersen failed its primary endpoint in phase 3 in September 2026, whereas obudanersen and rugonersen are continuing in phase 3 trials, with REVEAL results expected by the sponsor in the second half of 2027 [24, 26, 27, 85, 86]. No medicinal product is authorised for these syndromes, and symptomatic drugs are used by extrapolation of evidence, sometimes outside the approved indication. The French PNDS documents of 2021 and 2022 are the only national diagnosis and care protocols for AS and dup15q; they provide consensus recommendations on the choice of antiseizure medications, drugs to avoid, early augmentative communication, dental and orthopaedic care and visit frequency, and diverge from the North American sources mainly on first-line antiseizure treatment and on the melatonin dose.

In maternal dup15q, idic(15) is associated with severe hypotonia, ASD, severe intellectual disability, infantile spasms and refractory epilepsy with a risk of SUDEP, and interstitial duplication with a milder phenotype, inherited from the mother in approximately 15% of cases [2, 56]. In the BP1-BP2 microdeletion, accurate communication of risk, based on estimates of penetrance and effect size, prevents both underestimation and inappropriate causal attribution, and investigation for a second cause remains indicated in severe phenotypes [8, 28, 59]. Gaps persist in epidemiology outside Europe, North America and China and in adult natural history data.

13. Bibliographic References

1. Dagli AI, Mathews J, Williams CA. Angelman Syndrome. 1998 Sep 15 [updated 2021 Apr 22; revised 2025 May 1]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1144/ PMID: 20301323.
2. Lusk L, Vogel-Farley V, DiStefano C, Jeste S. Maternal 15q Duplication Syndrome. 2016 Jun 16 [updated 2021 Jul 15]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK367946/ PMID: 27308687.
3. Orphanet. Angelman syndrome (ORPHA:72) and etiological subtypes ORPHA:98794, 98795, 411515, 411511; prevalence data from Orphadata (en_product9_prev). Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/72
4. Orphanet. 15q11q13 microduplication syndrome (ORPHA:238446); Inverted duplicated chromosome 15 syndrome (ORPHA:3306); 15q11.2 microdeletion syndrome (ORPHA:261183); prevalence data from Orphadata (en_product9_prev). Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/238446
5. Cox DM, Butler MG. The 15q11.2 BP1-BP2 microdeletion syndrome: a review. Int J Mol Sci. 2015;16(2):4068-82. doi:10.3390/ijms16024068. PMID: 25689425.
6. Mertz LG, Christensen R, Vogel I, Hertz JM, Nielsen KB, Grønskov K, et al. Angelman syndrome in Denmark. birth incidence, genetic findings, and age at diagnosis. Am J Med Genet A. 2013;161A(9):2197-203. doi:10.1002/ajmg.a.36058. PMID: 23913711.
7. Depienne C, Moreno-De-Luca D, Heron D, Bouteiller D, Gennetier A, Delorme R, et al. Screening for genomic rearrangements and methylation abnormalities of the 15q11-q13 region in autism spectrum disorders. Biol Psychiatry. 2009;66(4):349-59. doi:10.1016/j.biopsych.2009.01.025. PMID: 19278672.
8. Rosenfeld JA, Coe BP, Eichler EE, Cuckle H, Shaffer LG. Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med. 2013;15(6):478-81. doi:10.1038/gim.2012.164. PMID: 23258348.
9. Angelman H. 'Puppet' children: a report on three cases. Dev Med Child Neurol. 1965;7(6):681-8. doi:10.1111/j.1469-8749.1965.tb07844.x.
10. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Angelman syndrome; p. 274–277.
11. Williams CA, Frias JL. The Angelman ("happy puppet") syndrome. Am J Med Genet. 1982;11(4):453-60. doi:10.1002/ajmg.1320110411. PMID: 7091188.
12. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Angelman syndrome; p. 346–348.
13. Knoll JH, Nicholls RD, Magenis RE, Graham JM, Lalande M, Latt SA. Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am J Med Genet. 1989;32(2):285-90. doi:10.1002/ajmg.1320320235. PMID: 2564739.
14. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Genomic imprinting, p. 30–31; Chromosomal mosaicism—prenatal, p. 654–659; Robertsonian translocations, p. 684–687.
15. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997;15(1):70-3. doi:10.1038/ng0197-70. PMID: 8988171.
16. Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS, et al. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nat Genet. 1997;15(1):74-7. doi:10.1038/ng0197-74. PMID: 8988172.
17. Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, et al. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140(5):413-8. doi:10.1002/ajmg.a.31074. PMID: 16470747.
18. Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet. 2019;27(9):1326-1340. doi:10.1038/s41431-019-0435-0. PMID: 31235867.
19. Battaglia A. The inv dup (15) or idic (15) syndrome (Tetrasomy 15q). Orphanet J Rare Dis. 2008;3:30. doi:10.1186/1750-1172-3-30. PMID: 19019226.
20. Doornbos M, Sikkema-Raddatz B, Ruijvenkamp CA, Dijkhuizen T, Bijlsma EK, Gijsbers AC, et al. Nine patients with a microdeletion 15q11.2 between breakpoints 1 and 2 of the Prader-Willi critical region, possibly associated with behavioural disturbances. Eur J Med Genet. 2009;52(2-3):108-15. doi:10.1016/j.ejmg.2009.03.010. PMID: 19328872.
21. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. Prader-Willi syndrome (commentary on 15q11.2 microdeletion and microduplication); p. 278–280.
22. Burnside RD, Pasion R, Mikhail FM, Carroll AJ, Robin NH, Youngs EL, et al. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet. 2011;130(4):517-28. doi:10.1007/s00439-011-0970-4. PMID: 21359847.
23. Butler MG. Magnesium Supplement and the 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome: A Potential Treatment?. Int J Mol Sci. 2019;20(12):2914. doi:10.3390/ijms20122914. PMID: 31207912.
24. Hipp JF, Bacino CA, Bird LM, Bruenig-Traebert I, Chan D, de Wit MC, et al. The UBE3A-ATS antisense oligonucleotide rugonersen in children with Angelman syndrome: a phase 1 trial. Nat Med. 2025;31(9):2936-2945. doi:10.1038/s41591-025-03784-7. PMID: 40646322.
25. Samanta D. Emerging disease-modifying therapies for Angelman syndrome: A comprehensive review for pediatric neurologists. Brain Dev. 2026;48(3):104527. doi:10.1016/j.braindev.2026.104527. PMID: 41864145.
26. Ionis Pharmaceuticals. REVEAL: A Phase 3 Study of Obudanersen (ION582) in Angelman Syndrome. ClinicalTrials.gov identifier: NCT06914609. Available from: https://clinicaltrials.gov/study/NCT06914609
27. OHB Pediatrics Ltd. BEACON - Phase III Clinical Study of Rugonersen in Angelman Syndrome. ClinicalTrials.gov identifier: NCT07605429. Available from: https://clinicaltrials.gov/study/NCT07605429
28. Jønch AE, Douard E, Moreau C, Van Dijck A, Passeggeri M, Kooy F, et al. Estimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice. J Med Genet. 2019;56(10):701-710. doi:10.1136/jmedgenet-2018-105879. PMID: 31451536.
29. Butler MG. Clinical Presentation, Genetics, and Laboratory Testing with Integrated Genetic Analysis of Molecular Mechanisms in Prader-Willi and Angelman Syndromes: A Review. Int J Mol Sci. 2026;27(3):1270. doi:10.3390/ijms27031270. PMID: 41683698.
30. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Ataxic child, p. 74–75; Generalized disorders of skin pigmentation, p. 162–163; Microcephaly, p. 228–229; Obesity with and without developmental delay, p. 255; Seizures with developmental delay, p. 308–309; Rett syndrome, p. 520–521.
31. Buiting K, Williams C, Horsthemke B. Angelman syndrome - insights into a rare neurogenetic disorder. Nat Rev Neurol. 2016;12(10):584-93. doi:10.1038/nrneurol.2016.133. PMID: 27615419.
32. Jiang Y, Lev-Lehman E, Bressler J, Tsai TF, Beaudet AL. Genetics of Angelman syndrome. Am J Hum Genet. 1999;65(1):1-6. doi:10.1086/302473. PMID: 10364509.
33. Matos EMSS, Albuquerque LS, Ribeiro EM. Síndrome de Angelman. In: Ribeiro EM, coordinator. Síndromes Genéticas: Reconhecer para Tratar. Fortaleza: EdUnichristus; 2021. p. 50–52.
34. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Syndrome d'Angelman. Saint-Denis La Plaine: HAS; 2021-12-01. Centre de Référence des Déficiences Intellectuelles de causes rares; Filière DéfiScience. Available from: https://www.has-sante.fr/jcms/p_3300845
35. Sánchez J, Fernández R, Madruga M, Bernabeu-Wittel J, Antiñolo G, Borrego S. Somatic and germ-line mosaicism of deletion 15q11.2-q13 in a mother of dyzigotic twins with Angelman syndrome. Am J Med Genet A. 2014;164A(2):370-6. doi:10.1002/ajmg.a.36281. PMID: 24311297.
36. Tang HS, Wang DG, Xie XM, Li DZ. Apparent germline mosaicism for a 15q11-q13 deletion causing recurrent Angelman syndrome in a Chinese family. Eur J Obstet Gynecol Reprod Biol. 2019;236:255-257. doi:10.1016/j.ejogrb.2019.02.029. PMID: 30890277.
37. Fridman C, Koiffmann CP. Origin of uniparental disomy 15 in patients with Prader-Willi or Angelman syndrome. Am J Med Genet. 2000;94(3):249-53. doi:10.1002/1096-8628(20000918)94:3<249::aid-ajmg12>3.0.co;2-x. PMID: 10995513.
38. Nazlican H, Zeschnigk M, Claussen U, Michel S, Boehringer S, Gillessen-Kaesbach G, et al. Somatic mosaicism in patients with Angelman syndrome and an imprinting defect. Hum Mol Genet. 2004;13(21):2547-55. doi:10.1093/hmg/ddh296. PMID: 15385437.
39. Le Fevre A, Beygo J, Silveira C, Kamien B, Clayton-Smith J, Colley A, et al. Atypical Angelman syndrome due to a mosaic imprinting defect: Case reports and review of the literature. Am J Med Genet A. 2017;173(3):753-757. doi:10.1002/ajmg.a.38072. PMID: 28211971.
40. Hosoki K, Takano K, Sudo A, Tanaka S, Saitoh S. Germline mosaicism of a novel UBE3A mutation in Angelman syndrome. Am J Med Genet A. 2005;138A(2):187-9. doi:10.1002/ajmg.a.30926. PMID: 16100729.
41. Keute M, Miller MT, Krishnan ML, Sadhwani A, Chamberlain S, Thibert RL, et al. Angelman syndrome genotypes manifest varying degrees of clinical severity and developmental impairment. Mol Psychiatry. 2021;26(7):3625-3633. doi:10.1038/s41380-020-0858-6. PMID: 32792659.
42. Lossie AC, Whitney MM, Amidon D, Dong HJ, Chen P, Theriaque D, et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J Med Genet. 2001;38(12):834-45. doi:10.1136/jmg.38.12.834. PMID: 11748306.
43. Bindels-de Heus KGCB, Mous SE, Ten Hooven-Radstaake M, van Iperen-Kolk BM, Navis C, Rietman AB, et al. An overview of health issues and development in a large clinical cohort of children with Angelman syndrome. Am J Med Genet A. 2020;182(1):53-63. doi:10.1002/ajmg.a.61382. PMID: 31729827.
44. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Supernumerary marker chromosomes (SMCs)—postnatal, p. 690–691; Supernumerary marker chromosomes (SMCs)—prenatal, p. 692–693.
45. Urraca N, Cleary J, Brewer V, Pivnick EK, McVicar K, Thibert RL, et al. The interstitial duplication 15q11.2-q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature. Autism Res. 2013;6(4):268-79. doi:10.1002/aur.1284. PMID: 23495136.
46. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Syndrome de duplication 15q. Saint-Denis La Plaine: HAS; 2022-12-13. Centre de Référence Anomalies du développement et syndromes malformatifs Sud-Est (CHU de Marseille) and Centre de Référence constitutif Déficiences intellectuelles de causes rares et polyhandicap; text of October 2022. Available from: https://www.has-sante.fr/jcms/p_3385231
47. Clinical Genome Resource (ClinGen). Dosage sensitivity curation: NIPA1 (HGNC:17043). Available from: https://search.clinicalgenome.org/kb/gene-dosage/HGNC:17043
48. Rainier S, Chai JH, Tokarz D, Nicholls RD, Fink JK. NIPA1 gene mutations cause autosomal dominant hereditary spastic paraplegia (SPG6). Am J Hum Genet. 2003;73(4):967-71. doi:10.1086/378817. PMID: 14508710.
49. Davis KW, Serrano M, Loddo S, Robinson C, Alesi V, Dallapiccola B, et al. Parent-of-Origin Effects in 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome. Int J Mol Sci. 2019;20(6):1459. doi:10.3390/ijms20061459. PMID: 30909440.
50. Glassman LW, Grocott OR, Kunz PA, Larson AM, Zella G, Ganguli K, et al. Prevalence of gastrointestinal symptoms in Angelman syndrome. Am J Med Genet A. 2017;173(10):2703-2709. doi:10.1002/ajmg.a.38401. PMID: 28816003.
51. Thibert RL, Conant KD, Braun EK, Bruno P, Said RR, Nespeca MP, et al. Epilepsy in Angelman syndrome: a questionnaire-based assessment of the natural history and current treatment options. Epilepsia. 2009;50(11):2369-76. doi:10.1111/j.1528-1167.2009.02108.x. PMID: 19453717.
52. Larson AM, Shinnick JE, Shaaya EA, Thiele EA, Thibert RL. Angelman syndrome in adulthood. Am J Med Genet A. 2015;167A(2):331-44. doi:10.1002/ajmg.a.36864. PMID: 25428759.
53. Fairbrother LC, Cytrynbaum C, Boutis P, Buiting K, Weksberg R, Williams C. Mild Angelman syndrome phenotype due to a mosaic methylation imprinting defect. Am J Med Genet A. 2015;167(7):1565-9. doi:10.1002/ajmg.a.37058. PMID: 25899869.
54. Conant KD, Finucane B, Cleary N, Martin A, Muss C, Delany M, et al. A survey of seizures and current treatments in 15q duplication syndrome. Epilepsia. 2014;55(3):396-402. doi:10.1111/epi.12530. PMID: 24502430.
55. DiStefano C, Wilson RB, Hyde C, Cook EH, Thibert RL, Reiter LT, et al. Behavioral characterization of dup15q syndrome: Toward meaningful endpoints for clinical trials. Am J Med Genet A. 2020;182(1):71-84. doi:10.1002/ajmg.a.61385. PMID: 31654560.
56. Friedman D, Thaler A, Thaler J, Rai S, Cook E, Schanen C, et al. Mortality in isodicentric chromosome 15 syndrome: The role of SUDEP. Epilepsy Behav. 2016;61:1-5. doi:10.1016/j.yebeh.2016.04.001. PMID: 27218684.
57. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Deletions and duplications (microdeletions); p. 661–665.
58. Chin HL, Chang J, Nordli D. Refining the electroclinical phenotype of 15q11.2 microdeletion: EEG biomarker overlap with Angelman syndrome. Epileptic Disord. 2026 [Epub ahead of print]. doi:10.1002/epd2.70328. PMID: 42434914.
59. Yu Y, Li M, Chang J, Zhang H, Zhou X, Jiang Y, et al. Prenatal diagnosis and estimated penetrance of 15q11.2 BP1-BP2 microdeletion syndrome in a Chinese cohort: a retrospective study and literature review. Hum Genomics. 2026;20(1):123. doi:10.1186/s40246-026-00997-w. PMID: 42231477.
60. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. Intellectual disability (Table 2.16); p. 188–190.
61. Yang M, Xiao Y, Chen C, Chu Z, Hu G. Case Report: Synergistic effects of an ASXL3 mutation and a 15q11.2 BP1-BP2 microdeletion in a severe neurodevelopmental phenotype. Front Genet. 2025;16:1674158. doi:10.3389/fgene.2025.1674158. PMID: 41458212.
62. Morales J, Pujar S, Loveland JE, Astashyn A, Bennett R, Berry A, et al. A joint NCBI and EMBL-EBI transcript set for clinical genomics and research. Nature. 2022;604(7905):310-315. doi:10.1038/s41586-022-04558-8. PMID: 35388217. MANE GRCh38 v1.5 file (UBE3A NM_130839.5; NIPA1 NM_144599.5) available from: https://ftp.ncbi.nlm.nih.gov/refseq/MANE/MANE_human/release_1.5/
63. National Center for Biotechnology Information. UBE3A (Gene ID 7337): RefSeq NM_130839.5/NP_570854.1 (isoform 3, 872 aa), NM_000462.5/NP_000453.2 (isoform 2, 875 aa) and NP_570853.1 (isoform 1, 852 aa). Bethesda (MD): NCBI; accessed on 6 October 2026. Available from: https://www.ncbi.nlm.nih.gov/gene/7337
64. Tan WH, Bird LM, Thibert RL, Williams CA. If not Angelman, what is it? A review of Angelman-like syndromes. Am J Med Genet A. 2014;164A(4):975-92. doi:10.1002/ajmg.a.36416. PMID: 24779060.
65. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 1, section 1.5.2.5; Chapter 44, sections 44.1.3 and 44.3.1.
66. European Medicines Agency. Medicines data (human medicines data file) and product information for Keppra (EMEA/H/C/000277), Buccolam (EMEA/H/C/002267) and Slenyto (EMEA/H/C/004425; SmPC, sections 4.1, 4.2 and 5.1). Amsterdam: EMA; accessed on 6 October 2026. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/slenyto
67. U.S. Food and Drug Administration. Prescribing information: Keppra® (levetiracetam; UCB, rev. 01/2026); Onfi® (clobazam; Lundbeck, rev. 03/2024); Valtoco® (diazepam nasal spray; Neurelis, rev. 06/2026); Nayzilam® (midazolam nasal spray; UCB, rev. 01/2023). Available from: https://dailymed.nlm.nih.gov/dailymed/
68. Manssen L, Pfarrer P, Gburek-Augustat J, Krey I, Nicolai L, Zaddach M, et al. Treatment responses to antiseizure medication in children with Angelman syndrome. Eur J Paediatr Neurol. 2026;65:1-7. doi:10.1016/j.ejpn.2026.09.001. PMID: 42771958.
69. Samanta D. How I treat Angelman syndrome: an expert opinion. Expert Opin Pharmacother. 2026;27(9):809-829. doi:10.1080/14656566.2026.2685074. PMID: 42234576.
70. Zydus Pharmaceuticals USA. Diazepam rectal gel (ANDA217468): prescribing information [revised 2026 Apr]. Silver Spring (MD): U.S. Food and Drug Administration; 2026 [accessed 2026 Oct 26]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=652714c7-25c4-4d05-979d-8eee3b6f2f4d
71. Sanofi – Produtos Farmacêuticos, Lda. Depakine 200 mg/ml solução oral (valproato de sódio): resumo das características do medicamento. Infomed, INFARMED, med_id 2413 [accessed 2026-10-18]. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=2413&tipo_doc=rcm
72. U.S. Food and Drug Administration. Zarontin (ethosuximide) capsules — prescribing information (NDA012380), version of 25 May 2026 [Internet]. Silver Spring (MD): FDA; accessed 2026-11-02. Available from: https://api.fda.gov/drug/label.json?search=openfda.brand_name:%22Zarontin%22
73. UCB Pharma Ltd. Nootropil 1200 mg film-coated tablets — Summary of Product Characteristics [Internet]. electronic medicines compendium (eMC); updated 01/07/2025. Available from: https://www.medicines.org.uk/emc/product/101131/smpc
74. INFARMED. Rubifen 10 mg comprimidos (metilfenidato): resumo das características do medicamento [Internet]. Lisboa: INFARMED, Infomed; text revised September 2025 [accessed 2026-10-18]. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=36077&tipo_doc=rcm
75. Peters SU, Bird LM, Kimonis V, Glaze DG, Shinawi LM, Bichell TJ, et al. Double-blind therapeutic trial in Angelman syndrome using betaine and folic acid. Am J Med Genet A. 2010;152A(8):1994-2001. doi:10.1002/ajmg.a.33509. PMID: 20635355.
76. Bird LM, Ochoa-Lubinoff C, Tan WH, Heimer G, Melmed RD, Rakhit A, et al. The STARS Phase 2 Study: A Randomized Controlled Trial of Gaboxadol in Angelman Syndrome. Neurology. 2021;96(7):e1024-e1035. doi:10.1212/WNL.0000000000011409. PMID: 33443117.
77. Keary C, Bird LM, de Wit MC, Hatti S, Heimer G, Heussler H, et al. Gaboxadol in Angelman syndrome: a double-blind, parallel-group, randomized placebo-controlled phase 3 study. Eur J Paediatr Neurol. 2023;47:6-12. doi:10.1016/j.ejpn.2023.07.008. PMID: 37639777.
78. Tan WH, Bird LM, Sadhwani A, Barbieri-Welge RL, Skinner SA, Horowitz LT, et al. A randomized controlled trial of levodopa in patients with Angelman syndrome. Am J Med Genet A. 2018;176(5):1099-1107. doi:10.1002/ajmg.a.38457. PMID: 28944563.
79. ClinicalTrials.gov. NCT05011851 — An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome [Internet]. Bethesda (MD): National Library of Medicine; accessed 2026-11-02. Available from: https://clinicaltrials.gov/study/NCT05011851
80. Ruiz-Antoran B, Sancho-López A, Cazorla-Calleja R, López-Pájaro LF, Leiva Á, Iglesias-Escalera G, et al. A randomized placebo controlled clinical trial to evaluate the efficacy and safety of minocycline in patients with Angelman syndrome (A-MANECE study). Orphanet J Rare Dis. 2018;13(1):144. doi:10.1186/s13023-018-0891-6. PMID: 30126448.
81. Grieco JC, Ciarlone SL, Gieron-Korthals M, Schoenberg MR, Smith AG, Philpot RM, et al. An open-label pilot trial of minocycline in children as a treatment for Angelman syndrome. BMC Neurol. 2014;14:232. doi:10.1186/s12883-014-0232-x. PMID: 25491305.
82. Ciarlone SL, Grieco JC, D'Agostino DP, Weeber EJ. Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model. Neurobiol Dis. 2016;96:38-46. doi:10.1016/j.nbd.2016.08.002. PMID: 27546058.
83. Ionis Pharmaceuticals. CHAMPION: A Study to Evaluate the Efficacy and Safety of Obudanersen (ION582) in Children and Adults With Angelman Syndrome due to Paternal Uniparental Disomy or Imprinting Defects. ClinicalTrials.gov identifier: NCT07782827. Available from: https://clinicaltrials.gov/study/NCT07782827
84. Ionis Pharmaceuticals. HALOS: Multiple Ascending Doses of ION582 in Participants With Angelman Syndrome. ClinicalTrials.gov identifier: NCT05127226. Available from: https://clinicaltrials.gov/study/NCT05127226
85. Ultragenyx Pharmaceutical Inc. Ultragenyx Announces Phase 3 Aspire results in Angelman Syndrome [press release]. Novato (CA): GlobeNewswire; 2026 Sep 2. Available from: https://finance.yahoo.com/healthcare/articles/ultragenyx-announces-phase-3-aspire-200100986.html (trial NCT06617429: https://clinicaltrials.gov/study/NCT06617429)
86. Ionis Pharmaceuticals. Second quarter 2026 financial results and business update [press release; exhibit 99.1 to Form 8-K]. Carlsbad (CA): Ionis; 2026 Jul 29. Available from: https://www.sec.gov/Archives/edgar/data/874015/000114036126029960/ef20078953_ex99-1.htm
87. Oak Hill Bio; Research Alliance Corp. III. Oak Hill Bio to combine with Research Alliance Corp. III to advance rugonersen in Angelman syndrome [press release; exhibit 99.1 to Form 8-K]. 2026 Jul 27. Available from: https://www.sec.gov/Archives/edgar/data/2118032/000119312526316954/d101725dex991.htm
88. MavriX Bio. A Phase 1/2 Study of the Safety and Efficacy of MVX-220 in Angelman Syndrome. ClinicalTrials.gov identifier: NCT07181837. Available from: https://clinicaltrials.gov/study/NCT07181837
89. Hoffmann-La Roche. A Study to Investigate the Pharmacokinetics and Safety and to Provide Proof of Mechanism of Alogabat in Children and Adolescents With Angelman Syndrome. ClinicalTrials.gov identifier: NCT05630066. Available from: https://clinicaltrials.gov/study/NCT05630066
90. Thodeson D, Lockard T, Koh S. Genomics of Complex Neurodevelopmental Disorders with Variable Epilepsy Phenotypes: A Clinical Review of Dup15q Syndrome. Genes (Basel). 2026;17(2):163. doi:10.3390/genes17020163. PMID: 41751547.
91. Demarest S, Jeste S, Agarwal N, Arkilo D, Asgharnejad M, Hsiao S, et al. Efficacy, safety, and tolerability of soticlestat as adjunctive therapy for the treatment of seizures in patients with Dup15q syndrome or CDKL5 deficiency disorder in an open-label signal-finding phase II study (ARCADE). Epilepsy Behav. 2023;142:109173. doi:10.1016/j.yebeh.2023.109173. PMID: 37011526.
92. Newleos Therapeutics; Hoffmann-La Roche. Basmisanil in Children and Adolescents With Dup15q Syndrome (phase II). ClinicalTrials.gov identifiers: NCT07846215 and NCT05307679. Available from: https://clinicaltrials.gov/study/NCT07846215
93. Das S, Shet V, Palakodeti S, Pokhrel P, Ansari M, Qutaish O, et al. Late onset psychosis in a case of 15q11.2 BP1-BP2 microdeletion (Burnside-Butler) syndrome: A case report and literature review. SAGE Open Med Case Rep. 2024;12:2050313X241229058. doi:10.1177/2050313X241229058. PMID: 38292875.
94. U.S. Food and Drug Administration. Drugs@FDA and openFDA: approval history and labels for Keppra (NDA 021035; label of 28/01/2026), Onfi (NDA 202067), Valtoco (NDA 211635; efficacy supplement of 15/04/2025; label of 03/06/2026) and Nayzilam (NDA 211321); melatonin search with no results. Accessed on 6 October 2026. Available from: https://api.fda.gov/drug/drugsfda.json
95. Kuroda Y, Ohashi I, Saito T, Nagai J, Ida K, Naruto T, et al. Deletion of UBE3A in brothers with Angelman syndrome at the breakpoint with an inversion at 15q11.2. Am J Med Genet A. 2014;164A(11):2873-8. doi:10.1002/ajmg.a.36704. PMID: 25099823.
96. Alraddadi M, Almohlesy L, Ashour A, Alsalamah A, Ramadan S, Alqahtani Y, et al. Paternal transmission of Angelman syndrome via a mosaic small supernumerary marker chromosome 15: a rare case of germline epigenetic reset failure and somatic rescue. Cytogenet Genome Res. 2026 [Epub ahead of print]. doi:10.1159/cgr/achag003. PMID: 42607004.
97. Johnson JP, Schoof J, Beischel L, Schwancke C, Goldberg J, Black L, et al. Detection of a case of Angelman syndrome caused by an imprinting error in 949 pregnancies analyzed for AS following IVF. J Assist Reprod Genet. 2018;35(6):981-984. doi:10.1007/s10815-018-1161-1. PMID: 29654525.
98. Vermeiden JP, Bernardus RE. Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection?. Fertil Steril. 2013;99(3):642-51. doi:10.1016/j.fertnstert.2013.01.125. PMID: 23714438.
99. Michelson M, Eden A, Vinkler C, Leshinsky-Silver E, Kremer U, Lerman-Sagie T, et al. Familial partial trisomy 15q11-13 presenting as intractable epilepsy in the child and schizophrenia in the mother. Eur J Paediatr Neurol. 2011;15(3):230-3. doi:10.1016/j.ejpn.2010.11.001. PMID: 21145272.
100. Fridman C, Kok F, Diament A, Koiffmann CP. [Angelman syndrome: a frequently undiagnosed cause of mental retardation and epilepsy. Case report]. Arq Neuropsiquiatr. 1997;55(2):329-33. doi:10.1590/s0004-282x1997000200025. PMID: 9629397.
101. Ortiz-Prado E, Iturralde AL, Simbaña-Rivera K, Gómez-Barreno L, Hidalgo I, Rubio-Neira M, et al. 15q Duplication Syndrome: Report on the First Patient from Ecuador with an Unusual Clinical Presentation. Case Rep Med. 2021;2021:6662054. doi:10.1155/2021/6662054. PMID: 34007283.
102. Prasad A, Grocott O, Parkin K, Larson A, Thibert RL. Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases. Am J Med Genet A. 2018;176(6):1327-1334. doi:10.1002/ajmg.a.38694. PMID: 29696750.
103. ERN ITHACA. European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability. Available from: https://www.ern-ithaca.eu
104. ERN EpiCARE. European Reference Network for rare and complex epilepsies. Available from: https://epi-care.eu
105. Angelman Syndrome Alliance. Available from: https://www.angelmanalliance.org
106. Foundation for Angelman Syndrome Therapeutics (FAST). Available from: https://cureangelman.org
107. Unique — Understanding Rare Chromosome and Gene Disorders. Available from: https://rarechromo.org