16p11.2 Microdeletion and Microduplication

Literature and regulatory information updated: 6 October 2026.

Proximal recurrent deletion 16p11.2 (BP4–BP5, ~600 kb; 593 kb 16p11.2 deletion syndrome), proximal reciprocal duplication 16p11.2, and, as a distinct entity, distal deletion and duplication 16p11.2 (BP2–BP3, ~220 kb, which include SH2B1)

0. Initial Reference Table

1. Introduction

The 16p11.2 region is one of the regions of the human genome in which the architecture of segmental duplications most frequently gives rise to recurrent rearrangements, and the proximal deletion of about 600 kb between breakpoints 4 and 5 (BP4–BP5) is today considered one of the most frequent known genetic causes of neurodevelopmental disorders and autism spectrum disorder (ASD) [1, 24]. The story of its discovery is the story of high-resolution cytogenomics itself: the deletion is not visible in the G-banded karyotype and could only be recognised when microarray comparative genomic hybridization (aCGH) and single-nucleotide polymorphism (SNP) platforms began to be applied to cohorts of patients and controls [1, 11].

The first published description was by Ghebranious and colleagues, from the Marshfield Clinic, who in 2007 reported a de novo microdeletion of approximately 593 kb in monozygotic male twins with aortic valve anomaly, epilepsy and mild intellectual disability; the authors mapped the deletion by aCGH, refined it by hemizygosity mapping, and proposed that it resulted from intrachromosomal recombination between two nearly identical 147 kb segmental duplications flanking the interval [25]. In the same year, Sebat and colleagues demonstrated that de novo copy-number variants (CNVs) were associated with autism (10% of patients with sporadic autism versus 1% of controls), paving the way for the identification of recurrent loci [26].

In February 2008, three independent studies established the association with autism. Weiss and colleagues, from 751 multiplex families from the Autism Genetic Resource Exchange, observed five 593-kb de novo deletions and confirmed them in 5 of 512 children referred to Boston Children's Hospital and in 3 of 299 people with autism in an Icelandic population sample, versus 2 of 18,834 unscreened Icelandic controls; the reciprocal duplication was found in 7 affected individuals from AGRE families and in 4 of 512 Boston children, and the authors estimated that these CNVs explained about 1% of cases [27]. Kumar and colleagues found the deletion in 4 of 712 probands with autism and in none of 837 controls, mapped the breakpoints at the margins of ~147 kb segmental duplications with greater than 99% identity, and found no features that distinguished a clinical subtype of autism [28]; Marshall and colleagues described the same CNV in the chromosomal structural variation of autism [29].

The initial perspective, centred on autism, was quickly expanded. In 2009, McCarthy and colleagues linked microduplication to schizophrenia, with a combined relative risk of 14.5 [15]. In 2010, Walters and colleagues described a form of obesity with high penetrance in carriers of the deletion, responsible for 0.7% of cases of morbid obesity (odds ratio of 43), and Bochukova and colleagues identified, in children with severe early-onset obesity, smaller and more distal deletions that included SH2B1, with hyperphagia and insulin resistance disproportionate to the degree of obesity [16, 30]. In 2011, Jacquemont and colleagues demonstrated that proximal duplication is associated with underweight, establishing the concept of “mirror phenotypes” dependent on gene dosage [14]. The Simons Variation in Individuals Project (Simons VIP), described in 2012 as a “genetics first” approach, allowed hundreds of carriers and their non-carrier family members to be characterised in a standardised way, and was the basis of much of the current quantitative data [13, 31, 32].

From a nosological point of view, the literature uses different designations. In this article, “16p11.2 deletion” and “16p11.2 duplication”, without any other qualifier, refer to the proximal interval BP4–BP5; the BP2–BP3 distal deletion and duplication, which include SH2B1 and were initially called “atypical”, are distinct entities, with their own coordinates, genes, penetrance and phenotype, and are treated in specific subsections [1–3]. GeneReviews covers only the proximal deletion; duplication and distal CNVs are described from published cohorts [1].

2. Molecular Genetics and Pathophysiology

2.1 Genomic architecture and rearrangement mechanism

The short arm of chromosome 16 is rich in segmental duplications, which predisposes it to several recurrent rearrangements [33]. The proximal BP4–BP5 deletion is mediated by non-allelic homologous recombination (NAHR) between low-copy repeats of ~147 kb with 99.5% sequence identity flanking it; reciprocal duplication results from the same mechanism at the same location [1, 11, 28]. The Oxford manual highlights that deletion and duplication are expected as reciprocal events of repeat-mediated recombination, but that duplication tends to be less penetrant, because trisomy is generally better tolerated than monosomy [11]. ClinGen sets the minimum coordinates of the recurrent deletion at GRCh38 chr16:29,638,676–30,188,531 (ISCN designation seq[GRCh38] del(16)(p11.2)); the size calculated from these positions may differ from the expected size because of segmental duplications at breakpoints, and the reported coordinates vary slightly with the microarray design [1, 4].

Regarding parental origin, Duyzend and colleagues showed, in 126 families, a strong maternal bias in the origin of de novo deletions (59/66, 89.4%), the highest so far observed for a microdeletion syndrome CNV, with no transmission bias in inherited CNVs; the finding is consistent with a hotspot of unequal recombination in female meiosis [34]. The topic is discussed again in section 8, because other sources differ on parental bias.

In addition to the BP4–BP5 interval, the 16p11.2 segment contains a distal BP2–BP3 interval of ~220 kb (GRCh38 chr16:28,811,314–29,035,178), with nine genes, and larger rearrangements mediated by other pairs of repeats (BP1–BP3 of ~550 kb, BP1–BP4 and BP1–BP5 of ~1.7 Mb), which should be considered distinct entities [5, 6, 35]. The proximal and distal intervals, separated by about 650 kb, are linked by chromatin loops demonstrated by 4C-seq, FISH and Hi-C; genes in the distal interval are contacted by viewpoints located in the proximal interval, and disruption of these interactions accompanies expression changes in proximal CNV carriers, which may contribute to phenotypic overlap between the two regions [8].

2.2 Gene content and dosage effect

The proximal deletion removes one copy of a segment with 25 annotated genes or transcripts, in addition to four genes contained in the flanking segmental duplications; Zufferey and colleagues report 29 genes, and the Ensembl (version 116, GRCh38.p14) query of ClinGen coordinates returns 30 coding entries, including three without an assigned symbol [1, 6, 7]. Most of these genes have dosage-dependent expression, and genes whose expression correlates with copy number are enriched in genes associated with ASD and ciliopathies [1, 8]. The pathogenic mechanism is the loss (or gain) of function of several genes simultaneously, and GeneReviews recognises that how the deletion leads to clinical manifestations remains largely unknown [1].

2.3 Driver genes, modifiers and the “second hit”

The current model is polygenic within the interval and modified by genetic background. In families with Simons VIP de novo deletion, the effect of the deletion was −1.7 standard deviations (SD) on cognitive ability, +2.2 SD on social behaviour (poorer score on the Social Responsiveness Scale) and −1.3 SD on neuromotor performance, in relation to the mid-parent mean, but the correlations between parents and probands were maintained (0.42 for full-scale IQ and 0.53 for verbal IQ), which shows that family background continues to modulate the outcome [49]. Duyzend and colleagues found a bias towards maternal transmission of secondary deletions (32 maternal versus 14 paternal) and nine probands with secondary CNVs that disrupted ASD or intellectual disability genes [34]. In the Dutch series of 100 cases, 4% had a second confirmed genetic diagnosis and 18% an additional variant of uncertain significance [2]. A 2025 analysis of 2455 individuals with primary variants, including probands with 16p11.2 deletion, showed that associations between secondary variants and phenotype differ depending on the context of the primary variant and the mode of ascertainment (clinical or population cohort) [50]. These findings support further investigation despite identification of a 16p11.2 deletion when the phenotype is more severe or atypical (section 5).

2.4 Pathophysiology by system

In the central nervous system, the deletion is associated with a diffuse increase in brain volume, with a greater effect on the white matter and thalami, and a thicker corpus callosum; the duplication is associated with the reciprocal pattern, with a thinner corpus callosum, smaller volume of white matter and enlarged ventricles [1, 51]. Ciliary dysfunction is a convergent mechanism: the expression of ciliary genes is altered in lymphoblastoid lines from carriers of proximal and distal deletions, and the length of the primary cilium in neural progenitor cells varies in opposite directions in deletion and duplication [8, 40]. Energy metabolism is the second axis: proximal deletion increases body mass index (BMI) independently of IQ and behaviour, duplication reduces it, and variations correlate with the expression of genes contained in the CNV, not with that of flanking genes [6, 14]. In the distal region, loss of SH2B1 reduces leptin and insulin signalling; in UK and Estonian biobanks, BP2–BP3 deletion carriers have higher BMI, earlier onset type 2 diabetes, worse glycaemic control despite greater drug use and higher cystatin C, and Mendelian randomisation indicates that lower expression of SH2B1 increases the risk of diabetes [52]. In the axial skeleton, TBX6 dosage below the haploinsufficiency threshold disrupts somite segmentation; in mice, the Tbx6+/− null heterozygote had a solitary kidney in 13% of cases, a proportion that rose to 29% in the compound heterozygous model with a hypomorphic allele [41, 43].

2.5 Heredity and related point variants

Transmission is autosomal dominant, with incomplete penetrance and variable expressivity; most proximal deletions are de novo, while most proximal duplications and distal deletions are inherited from a parent with a mild or apparently normal phenotype [1, 2]. Sequence variants in genes of the interval produce monogenic clinical phenotypes that partially overlap with the CNV phenotype and that should be described with HGVS nomenclature in the MANE transcript. The recurrent PRRT2 variant NM_145239.3:c.649dup, with protein consequence p.Arg217fs in ClinVar abbreviated notation (VCV000065758, reevaluated in August 2026, pathogenic/likely pathogenic, multiple submitters without conflict), is an example of a loss-of-function allele with the same mechanism as the deletion [37, 53]. In congenital scoliosis associated with TBX6, the second allele is a common haplotype defined by three variants (rs2289292, rs3809624 and rs3809627); the first corresponds, in the MANE NM_004608.4 transcript, to position c.1227 (synonymous substitution p.Pro409=), while the other two are located in the 5′ non-coding region and are usually reported by the identifier rs [41, 42, 54]. The ClinVar classification of these common isolated variants is benign or conflicting, which illustrates that a hypomorphic risk allele is not, in itself, a Mendelian pathogenic variant [54].

3. Clinical Spectrum and Manifestations by Organ System

3.1 BP4–BP5 proximal deletion: clinical overview and frequencies

There is no dysmorphic pattern that allows clinical diagnosis; the phenotype is dominated by developmental delay, speech and language disorders, psychiatric and behavioural disorders, motor coordination deficits and obesity that sets in throughout childhood [1, 24]. Frequencies depend on the method of ascertainment: cohorts recruited from patients referred for microarray overestimate severity, and carriers identified by cascade studies or in biobanks make it possible to estimate the “average” effect of the deletion [6, 55]. The following table summarises the frequencies from GeneReviews and the largest European and North American cohort published by Zufferey and colleagues (285 carriers, of which 72 were evaluated in detail, and 68 intrafamilial controls) [1, 6].

3.2 Development, cognition and language

The mean full-scale intelligence quotient (IQ) of carriers is approximately 2 SDs lower than that of family members without the deletion: 82.7 versus 109.5 (−26.8 points) in the Hanson and Hippolyte series cited by GeneReviews, and 76.1 versus 108.3 (−32 points in de novo carriers) in that of Zufferey [1, 6, 32]. The majority do not have an intellectual disability (IQ <70): around 20% meet the criteria for intellectual disability, 65% of which are mild and 35% moderate, and around 30% are in the normal range (IQ ≥85), because the variance in IQ is the same as that of the general population [6]. Verbal IQ (average 74) is lower than non-verbal IQ (average 83) [6]. There was no difference in IQ between probands referred for neurodevelopmental disorder and family members identified through cascade testing [6]. Independent walking begins, on average, at 20.5 months, with gross motor delay in 37.6% of European probands [6]; carriers have worse performance in functional motor tasks, lower endurance, slower walking and running, and worse balance than their siblings [1]. In a 2025 study with school-age children, 24 carriers had an average IQ of 71, discrepant profiles between verbal and non-verbal domains in 55% and, among the 19 with longitudinal data, 58% showed a trajectory of “growing into deficits”, with significantly lower scores in the second assessment [59]. Another study from 2025 confirmed fine and gross motor deficits from the first year of life, more pronounced in the deletion than in the duplication in the MABC-2 battery [60].

Motor speech disorder is the most specific trait. Childhood apraxia of speech coexists with articulatory and phonological disorders, occurs independently of ASD and non-verbal IQ and can persist into adulthood; a minority remain minimally verbal [1, 56]. The language disorder is broad, without a profile of strengths and weaknesses between subdomains, and the pragmatic language impairment is common even without a diagnosis of ASD [1].

3.3 Psychiatry and behaviour

In 217 children carrying the deletion compared with 77 family controls, the deletion increased the frequency of any psychiatric disorder (OR 8.9), ADHD (OR 4.0) and ASD (OR 39.9) [57]. In the British IMAGINE-ID study, which included 16p11.2 deletions and duplications among 13 CNVs associated with high neuropsychiatric risk, 80% of carriers had at least one psychiatric disorder (OR 13.8 compared with siblings), and the specific genotype explained only 5% to 20% of the trait variance, meaning that the behavioural profile is not specific to 16p11.2 [61]. The French PNDS for obesities of rare cause summarises the deletion as one of the obesity aetiologies with the greatest burden of neurodevelopmental disorders (more than 90% of carriers), dominated by developmental coordination disorder, speech-sound and expressive and receptive language disorders (present in 71% of carriers older than 3 years) and ASD, whose prevalence it estimates at about 40 times that of a control population, a value consistent with the OR of 39.9 in the Niarchou cohort [19, 57]. Anxiety, obsessive-compulsive disorder, oppositional defiant disorder, conduct disorder, and schizophrenia have been described but have not exceeded the frequency of population controls in studies cited by GeneReviews [1]. Carriers without ASD still present more autism-spectrum traits (insistence on sameness, restricted interests, repetitive behaviours) than non-carrier family members [1, 32].

3.4 Growth, obesity and metabolism

Birth weight is slightly lower than average (Z −0.61), but BMI Z-score is significantly increased at age 3.5 years and obesity affects more than half of carriers at age 7 years and 70–75% of adults, with morbid obesity in 45% of obese adults [6]. The rise in BMI can be sudden and sharp; hyperphagia was recorded in all 14 obese patients evaluated in the European centre, and patients eat more in the absence of hunger, without an increase in episodes of loss of eating control [1, 6]. Obesity does not correlate with IQ or behaviour [6]. In the population of patients with morbid obesity (BMI ≥40 kg/m² or BMI Z-score ≥4), the deletion explained 0.7% of cases, with an OR of 43 [30]. Final height is about 1 SD lower, although obese children show the prepubertal acceleration of height usual in childhood obesity [6]. In the 2024 Dutch series, only 29.5% of proximal deletion carriers were obese (mean age of onset 9.8 years), with 21.3% being overweight and hyperphagia in 41%, which the authors attribute to the young age of the cohort (75.8% under 18 years) [2]. Hyperinsulinaemic hypoglycaemia has been described as the presentation of the deletion [1]. A 2026 systematic review on eating behaviour in genetic obesity included the 16p11.2 deletion among the aetiologies with hyperphagia and Prader-Willi syndrome-like traits, but highlighted that available instruments, such as the Hyperphagia Questionnaire, were developed for Prader-Willi and do not capture the entire spectrum [62].

The generic French PNDS for obesities of rare cause (2021) places the 16p11.2 deletion in class A of its classification, which groups the causes in which the genetic link to the obesity or eating-behaviour phenotype is considered certain and the penetrance of that phenotype high; class B groups the forms of intermediate penetrance and class C the situations in which obesity is mainly multifactorial and secondary to ID or to psychotropic treatment [19]. The classification was built to prioritise aetiological investigation and its authors declare it provisional; it does not correspond to a measured penetrance, and the series with the least biased ascertainment show that some carriers, particularly in childhood, are not obese [2, 19]. The PNDS places the onset of weight gain at around 9 years, with acceleration in young adulthood, later than in obesities of the leptin–melanocortin pathway (first months or years of life) and in Prader-Willi syndrome (about 3 years) [19]; this age is close to the mean age of onset in the Dutch series (9.8 years), whereas the European cohort of Zufferey already showed an increased BMI Z-score at 3.5 years and obesity in more than half of carriers by 7 years, a difference that reflects the ascertainment of each cohort [2, 6]. Regarding eating behaviour, the PNDS describes a specific course: impaired satiety is present in the child, precedes obesity in the adolescent and becomes less frequent in the adult; there is eating in the absence of hunger, leading to hyperphagia without loss of control, accentuated by external social or sensory stimuli and by boredom [19]. To screen for these changes, the PNDS proposes simple questions addressed to caregivers and the 11-item Dykens Hyperphagia Questionnaire, completed by the caregiver, with the limitation already mentioned that it was developed for Prader-Willi syndrome [19, 62].

In adults from biobanks, 16p11.2 deletions were among the CNVs with the highest number of significant medical associations in the UK Biobank (seven phenotypes), with diabetes, hypertension, obesity and renal failure being the outcomes affected by the highest number of CNVs [63]. These data derive from middle-aged and older adults of white British or Irish ancestry and do not describe the natural history of patients diagnosed in childhood [63].

3.5 Nervous system: seizures, movement disorders and neuroimaging

In the Simons VIP cohort, 42% of carriers with epilepsy had the classic or atypical phenotype of self-limited (familial) infantile epilepsy, consistent with PRRT2 haploinsufficiency; the majority had controlled seizures with subsequent remission, pharmacoresistant epilepsy was rare, and seizures responded to phenobarbital, carbamazepine and oxcarbazepine [58]. In a Dutch series of 33 carriers, 3 (9%) had benign infantile epilepsy and none paroxysmal kinesigenic dyskinesia, while 6 of 12 patients with a PRRT2 point variant had dyskinesia; the authors conclude that ascertainment bias overestimates the penetrance of PRRT2 phenotypes in point variants and that the deletion shows incomplete penetrance of these phenotypes [37]. Neurological examination frequently reveals axial and appendicular hypotonia with hyporeflexia, impaired agility, sacral dimple, macrocephaly and cerebellar tonsillar ectopia [64].

The most frequent structural anomalies involve the posterior fossa and craniocervical junction (Chiari malformation type I, ectopia of the cerebellar tonsils, platybasia), present in 19 of 41 MRI scans reviewed in the Zufferey cohort; two patients with syringomyelia were described [1, 6]. In a study of 79 deletion carriers, tonsillar ectopia reached 30.7%, Chiari I malformation 9.3% and thick or dysmorphic corpus callosum 16%, and the presence of any of these findings was associated with worse functioning in daily life, communication and social skills [51].

3.6 Skeleton, kidney and other malformations

Malformations or major medical problems were present in 58% (76/130) of probands, but in only 26.3% (10/38) of carriers identified through cascade testing, without recurrent malformation sequence; the authors concluded that the deletion should not be seen primarily as a malformation syndrome, with the exception of vertebral anomalies (around 20%), which justify radiological and orthopaedic evaluation [6]. Congenital scoliosis with hemivertebrae is explained by the TBX6 compound inheritance model (section 2.2) [41]. Congenital anomalies of the kidney and urinary tract (CAKUT) were identified in approximately 25% of 12 Chinese carriers and 16% of 25 Caucasian or Hispanic carriers with renal data, values much higher than those of the general population [43]; in a genomic analysis of 2824 CAKUT cases, the 16p11.2 locus was among the six that explained 65% of genomic disease CNVs, with extensive pleiotropy [65]. Müllerian aplasia (Mayer–Rokitansky–Küster–Hauser syndrome) is associated with 16p11.2 microdeletions: 16p11.2 and 17q12 microdeletions were found in 4 of 38 (10.5%) isolated cases, and 16p11.2, 17q12 and distal 22q11.2 microdeletions in 5 of 25 (20%) syndromic cases [66, 67]. Smith classifies 16p11.2 CNVs, along with 1q21.1, 15q11.2, 15q13.3 and 16p13.3, as risk factors with low penetrance also for heart diseases such as tetralogy of Fallot, interpretable in a multifactorial model [68].

3.7 Neoplasms and other findings

In an analysis of 5585 children with neuroblastoma and 23,505 controls, the 16p11.2 deletion was present in 0.39% of cases and 0.03% of controls (OR 13.9; 95% CI 5.8–33.4), the association remaining in European ancestry; the deletion was mainly de novo, without parental bias, in the four sequenced trios [69]. The relative risk is high, but the absolute risk remains low because neuroblastoma is rare; GeneReviews does not include imaging screening or markers in surveillance, and the health supervision review recommends only attention to signs and symptoms at each visit [1, 18]. Isolated cases of seminoma, cholesteatoma, desmoid tumour, leiomyoma, Wilms tumour and bifocal intracranial germinoma have been published, without demonstrating a causal association [70]. A patient with 16p11.2 de novo deletion and CORO1A variant on the other allele presented severe combined immunodeficiency, which exemplifies the unmasking of a recessive allele by the deletion [46].

3.8 Proximal BP4–BP5 duplication

Reciprocal duplication is the CNV most frequently associated with ASD and schizophrenia, and is associated with lower BMI [1, 13]. In an international study of 1006 participants, which compared 270 duplication carriers with 102 intra-family controls and 390 deletion carriers with 244 controls, full-scale IQ was 26.3 points lower in probands with duplication compared to non-carrier family members and 11.4 to 16.2 points lower in non-proband carriers; the average effect was similar to that of the deletion (−22.1 points), but the variance was much greater, with 19.4 times more very low scores (≤40) and 2.0 times more scores above 100 [13]. About 30% met criteria for intellectual disability (mean IQ 78.8), and parental IQ explained about 36% of the variation in probands with inherited duplication [1, 13]. ASD was diagnosed in 20% of probands with a duplication and 16% of probands with a deletion, but probands with a duplication and ASD had lower IQ [13]. The most frequent diagnoses were intellectual impairment, motor delay and attention deficit hyperactivity disorder (ADHD) in children and anxiety in adults; adults with duplication generally have fewer deficits than the children through whom they were identified [1, 71]. Direct comparison in children showed ADHD (OR 2.7), global psychiatric disorders (OR 2.8) and psychotic symptoms (OR 4.7) more frequent in the duplication than in the deletion, with no difference in ASD (22% versus 26%) [57].

The risk of schizophrenia is the main difference compared to the deletion. Microduplication was found in 0.63% of schizophrenia patients in the initial cohort and 0.34% in the replication cohort, versus 0.03–0.04% of controls, with a pooled risk of 14.5 (95% CI 3.3–62), and additional association with bipolar disorder and autism; at least two cases of childhood-onset schizophrenia have been described [1, 15]. In a study of 41,321 individuals, both the proximal and distal CNV 16p11.2 achieved genome-wide significance for schizophrenia [72].

The growth phenotype mirrors the deletion. Among 138 carriers identified by intellectual disability, psychiatric disorders or in population cohorts, half of the boys under 5 years of age were underweight compatible with growth retardation, and adults had an 8.3 times higher risk of clinical underweight, with food selectivity and reduced head circumference [14]. Microcephaly, white matter abnormalities and enlarged ventricles, action tremor, hyperreflexia and seizures (about 20% according to GeneReviews; 15%, 16 of 106, with epilepsy in 10% in the Simons VIP cohort) complete the neurological picture [1, 51, 58, 64]. A computerised neurocognitive battery applied in an international consortium showed that the 16p11.2 duplication has greater specific deficits than the deletion, especially in complex cognition, and lower processing speed [73]. Fetal ultrasound findings are rare: in a series of 20,884 prenatal diagnoses, none of the five fetuses with duplication had ultrasound changes [74].

3.9 BP2–BP3 distal deletion and duplication (SH2B1)

The distal deletion has been described in children with early-onset severe obesity: in 300 Caucasian patients with early-onset severe obesity (143 with developmental delay), five had overlapping deletions that included SH2B1, found in 2 of 7366 controls; the deletion cosegregated with obesity in three families, was found in two more of 1062 patients with isolated severe obesity, and the carriers had hyperphagia and insulin resistance disproportionate to obesity [16]. In a clinical laboratory, the deletion was identified in 31 of 23,084 patients, with inherited events and de novo; the six with detailed clinical data had developmental delay and four had BMI ≥ 95th percentile [33]. Barge-Schaapveld and colleagues proposed renaming the “atypical 16p11.2 deletion” as “distal 16p11.2 deletion”, describing developmental delay, behavioural problems, prominent forehead and narrow, downslanting palpebral fissures [3].

In the largest phenotyped series (88 deletions and 49 duplications, unrelated), distal CNVs were associated with ASD (26% and 22%, against 1.5% in the population) and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly, similar to those of the proximal region [8]. The distal deletion also increases the risk of schizophrenia: 13 of 13,850 patients versus 3 of 19,954 controls (OR 6.25; 95% CI 1.78–21.93), in an analysis based on Ashkenazi and Bulgarian cohorts [75]. In the Dutch series, the 19 distal deletion carriers analysed had obesity in 73.7% (mean onset at 5.1 years; BMI Z-score +3.2), hyperphagia in 61.1%, intellectual disability in 40% of the 10 with available IQ, ASD in 22.2%, visual problems in 63.2%, sleep problems in 57.9% and epilepsy in 15.8%; compared with proximal deletion carriers, they had more frequent, earlier and more severe obesity, greater stature and more motor delay [2]. In seven children and young people with a deletion that included SH2B1, severe obesity was present at 5 years, with hyperinsulinaemia in five, type 2 diabetes in one, dyslipidaemia in four and hepatic steatosis in four [76]. In adults from biobanks, the BP2–BP3 deletion was associated with early-onset, difficult-to-control type 2 diabetes and elevated cystatin C (section 2.4) [52]. The Oxford manual describes, in deletions that remove SH2B1 and in heterozygous variants of the gene, hyperphagia, obesity, disproportionate insulin resistance, mild speech delay and aggressive behaviour, and refers to acanthosis nigricans as a sign of insulin resistance [48]. The generic French PNDS for obesities of rare cause lists the 16p11.2 microdeletion including SH2B1 as a separate class A entity, with autosomal dominant transmission; the interval is given as 28.7–28.9 Mb, in coordinates of an earlier genome assembly, corresponding in the ClinGen GRCh37 coordinates to 28.82–29.05 Mb, so the laboratory report should always state the genome build [5, 19].

Distal duplication is less characterised: ClinGen attributes only limited evidence of triplosensitivity to it, the estimated Bayesian penetrance is 11.2%, and the Bachmann-Gagescu series did not find it enriched in patients compared to controls [5, 12, 33]. Larger CNVs that encompass both intervals (BP1–BP5, ~1.7 Mb) are associated with more severe phenotypes, and deletions of more than 8 Mb that include 16p11.2–p12.2 constitute another syndrome [1, 35].

4. Clinical Recognition and Red Flags

Recognition is almost always laboratory-based, because the deletion does not produce a facial gestalt; most diagnoses result from a microarray ordered for developmental delay, intellectual disability, or ASD [1]. GeneReviews and the health supervision review suggest considering the deletion in the presence of motor speech disorder, in particular childhood apraxia of speech, language disorder, learning difficulties or intellectual disability, social difficulties with or without ASD, macrocephaly, Chiari I malformation or tonsillar ectopia, epileptic seizures, vertebral anomalies, adolescent-onset obesity in the context of developmental delay, and breath-holding spells [1, 18]. Neurologically, sacral dimple, hypotonia with hyporeflexia, and reduced agility are useful clues [64]. In a child with paroxysmal kinesigenic dyskinesia and language delay, ASD, or intellectual disability, negative PRRT2 sequencing does not exclude the deletion, because sequencing does not detect dosage losses; a microarray should be ordered [47]. In the context of obesity, the French PNDS for obesities of rare cause regards as suggestive of a rare genetic cause isolated obesity before 3 years with a rapid rise in BMI from the first year without deceleration, or obesity before 6 years associated with eating-behaviour disorders, a neurodevelopmental disorder, a neurosensory deficit, a malformation syndrome or signs of hypothalamic-pituitary dysfunction; it defines severity in the child as a BMI above the IOTF 30 curve or a BMI Z-score ≥+3 SD and in the adult as a BMI >35 kg/m², and gives weight to the combination of early onset, rapid progression, severity, resistance to conventional treatment and eating-behaviour disorder, because each of these alone is common in common obesity [19]. The history should include the family tree with relatives' BMI, the corpulence curve from the child health record (absent adiposity rebound or rebound before 3 years, age at crossing the IOTF 30 curve), head circumference at birth, and enquiry into impulsive or compulsive eating behaviours, food seeking and night-time eating [19]. Because weight gain in the proximal deletion begins, on average, later, a child with a speech or language disorder and a rising BMI at school age may not meet the early-onset criteria; it is the associated developmental delay that should prompt the microarray [1, 19].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Diagnostic criteria

The diagnosis is established by identifying a heterozygous deletion of ~593 kb at the approximate coordinates GRCh38 chr16:29,638,676–30,188,531 [1]. There are no clinical criteria; the diagnosis is exclusively genomic. The duplication and the distal CNVs are defined in the same way by their respective coordinates, and ClinGen scores the proximal deletion and duplication, and the distal deletion, with sufficient evidence of dosage sensitivity (score 3), while the distal duplication is scored 1 [4, 5]. The ACMG and ClinGen technical standards for constitutional CNVs introduce a quantitative evidence-based scoring system, recommend the five classes used for sequence variants, and propose separating CNV classification from its implications for a specific patient, which is particularly useful for these CNVs of incomplete penetrance [77]. In the pathway proposed by the French PNDS for obesities of rare cause, obesity with a neurodevelopmental disorder, and especially with ID, should be referred to a genetics service linked to a reference or competence centre of the DéfiScience network, following the decision trees of the generic PNDS for polyhandicap and for ID and of the French association of molecular genetics (ANPGM); severe early-onset obesity without a neurodevelopmental disorder is investigated with gene panels that include the class A and B entities, and the indication may be discussed at a multidisciplinary consultation meeting with the support of the online tool Obsgen [19]. In this framework, the 16p11.2 deletion is detected by the microarray of the first branch, and a sequencing panel without CNV calling does not identify it [1, 19].

5.2 Available tests and limitations

The Oxford manual reproduces the 2010 consensus algorithm that established the microarray as a first-line test: excluding recognisable syndromes, family history of rearrangement and multiple miscarriages, an anomalous CNV should be confirmed if necessary, parents should be studied to determine whether it is inherited or de novo and the mechanism, and CNVs inherited from unaffected parents require consideration of incomplete penetrance, recessive allele unmasking, imprinting, amplification of parental duplication or complex inheritance [11, 78]. The European guideline on constitutional cytogenomic analysis recommends genomic array as a first-line test for patients with intellectual disability, autism, neurodevelopmental disorders or congenital anomalies, due to its higher diagnostic yield, and requires that prior counselling addresses uncertain results and incidental findings [79]. The ACMG recommends considering the exome or genome as a first or second-line test in paediatric patients with congenital anomalies or developmental delay/intellectual disability, which only detects 16p11.2 when the laboratory applies and validates the CNV calling [17]. The yield of high-resolution microarray as a first-line test in intellectual disability is around 18% on average, and 16p11.2 recurrent CNVs are among the most frequent in this context [81].

5.3 Genetic report and nomenclature

The report should indicate the type of CNV (loss or gain), the genomic coordinates with the reference genome version (GRCh37 or GRCh38) and ISCN nomenclature, the ACMG/ClinGen classification, the recurrent designation (BP4–BP5 or BP2–BP3), the need for parental study, and the limitations (e.g., undetectable low-level mosaicism) [1, 77, 79]. The European guideline adds that, for intragenic imbalances detected by array, MLPA or exome-based CNV analysis, the HGNC symbol and the reference transcript are indicated [79]. As the coordinates vary with the array design, a deletion of 533.9 kb, 544 kb or 604 kb within the interval, such as those reported in the cases in section 10, corresponds to the same recurrent CNV [47, 70]. For point variants of genes in the interval, the MANE transcript with version must be used: PRRT2 NM_145239.3, TBX6 NM_004608.4, KCTD13 NM_178863.5, CORO1A NM_007074.4 and SH2B1 NM_001387430.1 [7].

5.4 Interpretation: penetrance, mosaicism and additional causes

The proximal deletion is considered pathogenic, but the penetrance for “abnormal phenotype” was estimated at 46.8% (95% CI 31.5–64.2) in a Bayesian model that compared 146 of 33,226 postnatal aCGH cases (0.44%) with 6 of 22,246 controls (0.03%) and assumed a baseline risk of congenital anomalies, developmental delay or intellectual impairment of around 5% [11, 12]. The estimate does not measure the likelihood of subclinical effects: in carriers from the general population, the deletion maintains an effect on IQ similar to that in probands [6, 55]. Parental mosaicism can go unnoticed: in a Dutch family, a deletion considered de novo in 2013 was revealed, nine years later, to be inherited from a mother with mosaicism detected by SNP array, and Shinawi and colleagues found two probands with apparent mosaicism of the deletion in the blood [2, 82]. GeneReviews notes that the study of parental leucocytes may not detect somatic mosaicism and does not detect exclusively germline mosaicism [1]. When the phenotype is disproportionate (for example, severe intellectual impairment, multiple malformations or marked short stature), a second diagnosis should be considered: in the Dutch series, among others, PTPN11-related Noonan syndrome, TBX22-related X-linked cleft palate and PIK3CD-related immunodeficiency were identified [2].

6. Differential Diagnosis

The differential diagnosis is broad, because cardinal manifestations (developmental delay, ASD, obesity) are common; GeneReviews lists all chromosomal abnormalities and intellectual disability genes [1]. The table organises the differential diagnosis according to the clinical features that most frequently motivate the evaluation.

7. Treatment and Risk Management Strategies

7.1 Principles and hierarchy of sources

There is no treatment targeting CNV, and GeneReviews states that no clinical practice guidelines have been published for the 16p11.2 deletion; management is symptomatic, oriented towards identified deficits and based on a multidisciplinary team [1]. In 2023, Simons Searchlight and the 16p11.2 Genetic Foundation published a health supervision review for primary care, organised by age; it is a author consensus document, not a guideline with a formal grading of evidence, and some of its suggestions are based on small or pre-clinical studies, which is noted below [18]. There are no specific documents for duplication and distal CNVs; the same assessments are applied by extrapolation, adjusted to the phenotype (for example, monitoring for underweight in duplication and glucose metabolism in distal deletion) [2, 52].

The generic French PNDS «Obésités de causes rares», prepared by the PRADORT reference centre and published by the Haute Autorité de Santé in 2021, is not specific to this CNV: it applies common recommendations for diagnosis, assessment, treatment and follow-up to all rare genetic and lesional obesities, and cites the 16p11.2 deletion as an example at several points (age of onset, eating behaviour, neurodevelopmental disorders, bariatric surgery and setmelanotide trials) [19]. Its recommendations are expert consensus and apply here to carriers with established obesity or at risk of it. The divergences from the other sources are as follows: (1) age at onset of obesity of about 9 years in the PNDS, against a BMI Z-score already increased at 3.5 years in the Zufferey cohort [6, 19]; (2) inclusion in class A, which presupposes high penetrance of the obesity phenotype, against 29.5% obesity in a predominantly paediatric Dutch series and a Bayesian penetrance of 46.8% for an abnormal phenotype [2, 12, 19]; (3) metabolic assessment extended to all patients with obesity of rare cause (including liver, kidney, uric acid and vitamin D) and specialist follow-up at least every six months in the child, against glucose and haemoglobin A1c in overweight carriers in GeneReviews and a metabolic panel from 12 years with BMI above the 95th centile in the 2023 review [1, 18, 19]; (4) ECG and echocardiogram in the asymptomatic patient with obesity and repetition every 3–5 years, against echocardiography only in the presence of signs of heart disease in GeneReviews and in the newborn in the 2023 review [1, 18, 19]; (5) an explicit position against bariatric surgery in rare obesities with a neurodevelopmental disorder, save in exceptional cases, a matter not addressed by GeneReviews or the 2023 review [1, 18, 19]; (6) the regulatory status of the drugs dated 2021, since superseded by the indication extensions and by the negative result of EMANATE (section 7.5) [19, 22].

7.2 Assessment after diagnosis

Renal ultrasound is not included in the 2021 GeneReviews tables; later data on CAKUT in 16–25% of carriers with renal assessment, attributed to TBX6 gene dosage, were published after this review and constitute an argument for considering renal assessment, without a guideline having yet incorporated it [43, 65].

7.3 Neurodevelopment, speech and behaviour

Early intervention (0–3 years) with occupational therapy, physiotherapy and speech therapy, followed by preschool education with an individual educational plan, is the basis of treatment; administrative details described by GeneReviews are for the United States and vary between countries [1]. Apraxia of speech requires therapy aimed at speech motor planning; augmentative and alternative communication should be considered in patients with severe expressive difficulties, which does not harm speech development [1, 56]. The 2023 review recommends neurocognitive and neuropsychiatric assessment at diagnosis and annually, assessment of auditory processing at around 3 years of age and visual processing at around 4 years of age, and explains to families that, in a de novo deletion, the expected IQ is up to approximately 2 SDs below the family mean [18, 49]. Interventions used in ASD, such as applied behaviour analysis (ABA), can benefit these children, and ADHD can be treated with the usual medications [1]. The 2023 review states that stimulants can improve, in addition to attention, speech, coordination and social reciprocity, but this statement is based on an isolated study and not on controlled trials in this CNV [18].

The French PNDS for obesities of rare cause reserves psychotropic drugs for failure of psychoeducational strategies or for acute decompensation, prescribed by a psychiatrist, and gives guidance that applies to deletion carriers with obesity: for anxiety or depression, prefer a selective serotonin reuptake inhibitor at the lowest effective dose, with regular reassessment; avoid benzodiazepines because of the risk of respiratory depression, especially with untreated sleep apnoea; for severe behavioural disorders or schizophrenia-spectrum disorders, use an atypical antipsychotic (risperidone or aripiprazole) as first line, with metabolic and neurological monitoring (dyskinesia, dystonia, akathisia), aripiprazole being preferred for its better metabolic profile and haloperidol to be avoided; and limit polypharmacy, because people with neurodevelopmental disorders frequently show absent, excessive or paradoxical responses [19]. The PNDS gives no doses; the US labels do not include the 16p11.2 deletion, and the closest paediatric indication is irritability associated with autistic disorder, whose doses apply here by declared extrapolation: aripiprazole (Abilify®), from 6 to 17 years, orally once daily, starting at 2 mg/day, increased to 5 mg/day and, if necessary, to 10 or 15 mg/day, with adjustments of up to 5 mg/day at intervals of at least one week, a recommended range of 5 to 15 mg/day and half the usual dose in CYP2D6 poor metabolisers [84]; risperidone (Risperdal®), from 5 to 17 years, orally in one or two daily doses, starting at 0.25 mg/day below 20 kg or 0.5 mg/day at 20 kg or more, increased after at least 4 days to 0.5 or 1 mg/day respectively, maintained for 14 days, and subsequent increases of 0.25 or 0.5 mg/day at intervals of at least 2 weeks, with an effective range of 0.5 to 3 mg/day, for which the label gives no separate maximum, and no data below 15 kg [85]. In the EU, risperidone is authorised from 5 years only for the short-term (up to 6 weeks) symptomatic treatment of persistent aggression in conduct disorder in children and adolescents with subaverage intellectual functioning or intellectual disability, with a starting dose of 0.25 mg/day below 50 kg (optimum 0.5 mg/day; maximum 0.75 mg/day) and of 0.5 mg/day from 50 kg (optimum 1 mg/day; maximum 1.5 mg/day); autism spectrum disorder is not a European indication [86]. Both cause weight gain and metabolic changes, which in this CNV requires measuring weight, BMI, glucose and lipids before and during treatment [19, 84, 85].

7.4 Epilepsy and paroxysmal dyskinesia

Seizures are treated with standard anti-seizure drugs; none have demonstrated specific efficacy in this CNV [1]. In the Simons VIP cohort, most epilepsies were controlled and remitted, and seizures of self-limited infantile epilepsy responded to phenobarbital, carbamazepine, and oxcarbazepine [58]. For paroxysmal kinesigenic dyskinesia, the deletion GeneReviews suggests low doses of carbamazepine or phenytoin, and the PRRT2-related disorder GeneReviews suggests sodium channel blockers (carbamazepine or oxcarbazepine) as first line, with control in most patients with the PRRT2 point variant at doses of about 100 mg/day or lower, below the doses used for epilepsy [1, 36]. The application of this dose to the deletion is an extrapolation, and paroxysmal dyskinesia does not appear in the indications in the American prescribing information for carbamazepine (epilepsy and trigeminal neuralgia), so it is an off-label use [87]. The label includes boxed warnings for serious skin reactions (toxic epidermal necrolysis and Stevens-Johnson syndrome, with association to the HLA-B*15:02 allele in patients of Asian descent, which should be investigated prior to initiation in these populations) and for aplastic anaemia and agranulocytosis [87]. In the patient described in section 10.2, carbamazepine up to 250 mg/day improved episodes but worsened anxiety, and reintroduction up to 200 mg/day was followed by leucopenia [47].

7.5 Prevention and treatment of obesity

Obesity is the leading cause of medical morbidity in adults and can be worsened by medications used to manage behavioural symptoms [1]. GeneReviews recommends starting early, before excessive weight gain, nutritional counselling with normal portions, limiting intake between meals and an active lifestyle, with close supervision of portions and timings, given the increase in intake in the absence of hunger [1]. The 2023 review adds that changes in satiety precede obesity and should serve as a sign to control portions, and recommends referral to a nutritionist before a significant increase in BMI Z-score [18]. Psychotropic drugs that cause weight gain, such as clozapine or olanzapine, should be avoided when possible; the Dutch series also recommends caution with obesogenic psychotropic drugs in deletion and with anorectic drugs in duplication [1, 2].

The French PNDS for obesities of rare cause uses the 16p11.2 deletion as an example of eating-behaviour changes that can appear before weight gain and therefore recommends dietetic follow-up from diagnosis, maintained throughout life [19]. The principles are control of access to food, a regular, structured meal rhythm within a predictable framework that reduces anxiety, early management of behavioural difficulties and consistency between home, school and institutions, with an individualised support plan at school; in the child, the aim is to stabilise weight while height increases, and locking access to the kitchen or limiting extras should be discussed early with the parents [19]. In adolescents and adults without ID, the principles of common obesity apply (portion control, reduction of energy-dense foods and of sugary or alcoholic drinks, fibre-rich foods and water), with attention to eating without hunger and to avoiding boredom and external stimuli such as buffets and food shops; measurement of resting energy expenditure by indirect calorimetry can adjust the prescription when expenditure is lower than predicted; with ID, eating behaviour is assessed with the caregiver and, if necessary, during an inpatient observation stay, and the dietary framework is extended to residential and day-care settings [19]. Physical activity should be personalised and prescribed as adapted physical activity; for an adult without a neurodevelopmental disorder, the PNDS gives as an example walking 20 minutes a day when commuting, two supervised weekly sessions of resistance and muscle-strengthening exercise, less than 2 hours a day of screen time and getting up at least once an hour; with a neurodevelopmental disorder, it favours playful and varied activities (dance, music, water activities, motor circuits), routines and planning with pictograms, individual sessions when there is a behavioural disorder, and prior cardiological assessment when there is heart disease [19].

The durability of weight loss has been low: in Zufferey's cohort, two adults who underwent bariatric surgery regained weight several years later, and an adolescent who lowered his BMI from 39.5 to 27.7 kg/m² with diet and intense physical activity returned to his initial weight two years after stopping the regimen [6]. The PNDS cites data from the Swedish Obese Subjects (SOS) study for the 16p11.2 deletion: weight results similar to those of controls in the short term and inferior at 10 years [19]. The primary source is the analysis by Kristensson and colleagues: among 1843 operated SOS participants with available DNA, MLPA identified 9 deletion carriers (0.49%; 4 men and 5 women, none with a prior diagnosis of syndromic obesity), who at baseline had higher BMI, fasting insulin and systolic blood pressure and were operated on by vertical banded gastroplasty (4), gastric banding (3) or gastric bypass (2); at 1 year, the percentage excess BMI loss was 71.9% in carriers and 62.2% in non-carriers (37.9 versus 30.6 kg; p = 0.031), and at 10 years, after partial regain in both groups, it was 25.5% versus 41.5% (15.7 versus 21.3 kg), with no significant difference (p = 0.377), with follow-up rates of 86% and 82% [88]. Changes in risk factors and perceived health status were similar; the two carriers with type 2 diabetes went into remission at 2 years and relapsed by 10 years [88]. With a sample of 9 carriers, the authors concluded that bariatric surgery is a treatment option in this deletion, a less restrictive reading than that of the PNDS [19, 88]. In rare obesities with a neurodevelopmental disorder, the PNDS does not recommend bariatric surgery, save in exceptional cases, because the benefit–risk balance is unfavourable (medium- and long-term weight regain, physical and psychological vulnerability, poorly studied nutritional deficiencies and psychiatric decompensation, postoperative complications that are harder to diagnose), and requires the decision to be taken with a specialised centre, weighing the pharmacological treatments in development [19]. No anti-obesity drug has a specific indication for these CNVs; their use in carriers with obesity falls under the general obesity indications in the labels, when age, weight and BMI criteria are met, and efficacy in this population is extrapolated from small series [89–91]. In a Dutch series of adults with genetic obesity treated with liraglutide 3.0 mg/day, the two patients with a 16p11.2 deletion (one with a typical deletion and one with a distal deletion) were part of a group of four in which all lost at least 5% of their weight [2, 91]; in a subsequent real-world study of 23 adults with molecularly confirmed genetic obesity, liraglutide reduced weight by a median of 4.7% after 12 weeks at the maximum dose, without stratification by CNV [92]. In the pharmacological annex of the PNDS, dated 2021, liraglutide 3 mg/day was indicated in common obesity and usable in rare obesities without reimbursement (the annex dates the authorisation to March 2021, but the European marketing authorisation of Saxenda®, valid in France, dates from 23/03/2015 [90]), semaglutide 2.4 mg/week was awaiting a cohort temporary authorisation for use for common obesity with BMI >40 kg/m² without diabetes, and setmelanotide was in trials for SH2B1 alterations, including the 16p11.2 deletion; subsequent regulatory and trial data are given in the following table and in section 7.9 [19, 22].

GLP-1 analogues have a boxed warning on US labels for thyroid C-cell tumours in rodents and are contraindicated with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2; the serious adverse effects described include acute pancreatitis, acute gallbladder disease, acute kidney injury due to volume depletion, increased heart rate, hypersensitivity reactions and pulmonary aspiration during anaesthesia or deep sedation, and the most frequent effects are gastrointestinal [89, 94]. The semaglutide label also includes monitoring of behaviour and suicidal ideation, a relevant recommendation in a population with a high psychiatric burden, and both should be discontinued when pregnancy is recognised, semaglutide at least 2 months before a planned pregnancy [89, 94]. The Endocrine Society, in a 2017 guideline co-sponsored by the European Society of Endocrinology, considered that the use of weight loss drugs in paediatrics should be restricted to clinical trials; this position predates the paediatric approvals described above and should be read in light of them [98].

7.6 Metabolism, blood pressure and complications of obesity

In people who are overweight, monitoring includes fasting blood glucose and haemoglobin A1c, annually or as clinically indicated, and blood pressure at each visit; type 2 diabetes and hypertension are treated according to standard guidelines [1]. The 2023 review adds, from the age of 12 and with a BMI above the 95th percentile, annual testing with a basic metabolic panel, fasting lipids and haemoglobin A1c [18]. In distal deletion, early-onset and difficult-to-control diabetes and the elevation of cystatin C in biobanks justify closer metabolic and renal surveillance, even without a formal published recommendation [52, 76].

The French PNDS for obesities of rare cause organises metabolic surveillance by risk: in situations of moderate risk or with metabolic changes secondary to obesity, as is usually the case in this CNV, annual fasting glucose, C-peptide, haemoglobin A1c and lipid profile from adolescence and an oral glucose tolerance test every 5 years; in the presence of type 2 diabetes, annual fundoscopy, six-monthly microalbuminuria and clinically guided screening for cardiovascular complications [19]. Nutritional treatment is first line; in type 2 diabetes, metformin is the first-choice drug, GLP-1 analogues are the preferred option for their effect on weight and appetite, DPP-4 or SGLT2 inhibitors are add-on options not specifically studied in these obesities, and insulin is kept as a last resort or for insulinopenia; haemoglobin A1c is measured every 3 months, and with ID the regimen should be simple and supervised, with therapeutic education of caregivers [19]. The US metformin label indicates, in adults, starting with 500 mg twice daily or 850 mg once daily with meals, with increases of 500 mg weekly or 850 mg every 2 weeks up to a maximum of 2550 mg/day in divided doses, and, from 10 years, starting with 500 mg twice daily and weekly increases of 500 mg up to a maximum of 2000 mg/day in two doses; it should not be started with an estimated GFR between 30 and 45 mL/min/1.73 m² and is contraindicated below 30 [99]. In hypertriglyceridaemia, the PNDS recommends a fibrate with fasting triglycerides >5 mmol/L after 3 months of nutritional treatment and fenofibrate immediately with triglycerides >10 mmol/L or previous pancreatitis, with three-monthly triglycerides and dose adjustment if creatinine clearance is <60 mL/min; the US fenofibrate label (Tricor®) indicates, in severe hypertriglyceridaemia in adults, 48 to 145 mg once daily, maximum 145 mg/day, 48 mg/day in renal impairment, and does not establish safety or efficacy in the paediatric age group [19, 100]. In adults at high vascular risk, the LDL cholesterol target is <2.0 mmol/L, with a statin as first line and a six-monthly lipid profile [19].

The same PNDS adds liver, kidney and cardiac surveillance for all obesities of rare cause. Hepatic steatosis may appear earlier and be more severe than in common obesity; it recommends liver ultrasound, ALT, AST, GGT and ferritin, non-invasive assessment of fibrosis by simple scores in adults (such as FIB-4), not usable in children, and a hepatology opinion if fibrosis is suspected [19]. Annually, it recommends creatinine with estimated GFR (which is not validated in severe obesity and may be de-indexed for body surface area) and urine albumin or protein/creatinine ratio; nephrology referral is indicated with GFR <60 mL/min, a decline >5 mL/min/year, protein/creatinine ratio >100 mg/mmol or albumin/creatinine ratio >70 mg/mmol, persistent proteinuria on maximum-dose renin–angiotensin system blockade, uncontrolled hypertension, associated haematuria or structural renal lesions, a relevant point in this CNV because of the association with CAKUT; obesity-related glomerulopathy is treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker at progressive doses, with a blood pressure target <130/80 mmHg and a protein/creatinine ratio <50 mg/mmol [19, 43]. In the asymptomatic patient, it recommends at least one ECG and one transthoracic echocardiogram, to be repeated every 3–5 years or earlier if symptoms appear, and notes that BNP and NT-proBNP are inversely proportional to BMI, so that low values do not exclude heart failure at the usual thresholds [19].

7.7 Other manifestations

Chiari I malformation and syringomyelia are treated by neurosurgery and scoliosis by orthopaedics; the 2023 review suggests brain MRI if there are recurrent headaches [1, 18]. Hearing loss can be managed with hearing aids; the 2023 review suggests repeating hearing screening at 6 months and then annually, even after normal newborn screening [1, 18]. Sleep disorders (snoring, witnessed apnoea, daytime sleepiness) should be investigated at each consultation [18]. In the case of recurrent respiratory infections, the review recommends a blood count with differential count and immunoglobulin measurement, and, up to 5 years of age, a baseline measurement; it also suggests an annual blood count, ferritin and total iron binding capacity from 1 year onwards, due to the association between iron deficiency, breath-holding spells and sleep disturbance [18]. The same review mentions the discussion of probiotics with Lactobacillus reuteri and Enterococcus faecalis; this suggestion is based on works cited in the review and not on clinical trials in this CNV identified in the sources consulted, and should therefore not be presented as an established treatment [18].

The French PNDS for obesities of rare cause adds general measures that apply to carriers with obesity. For sleep, it recommends respiratory polygraphy or polysomnography when there are symptoms, with blood gases when hypoventilation is suspected, and continuous positive airway pressure for obstructive apnoea or non-invasive ventilation for hypoventilation; in children or when behaviour prevents a complete recording, it accepts home polygraphy with blood gases [19]. For the musculoskeletal system, it recommends examination of the spine, knees and feet, whole-body radiography (EOS) from 10 years whenever scoliosis is suspected, and, in any child with severe obesity and open growth plates who reports hip or knee pain or limping, anteroposterior and lateral radiographs of the pelvis and hips and urgent orthopaedic referral for suspected slipped capital femoral epiphysis; standard equipment has a limit of about 130 kg, above which bariatric equipment is needed [19]. In emergencies, difficulty in expressing symptoms and a high pain threshold make a recent change in behaviour (apathy, withdrawal, agitation) a possible sign of pain or somatic illness, which should be investigated before attributing the change to behaviour; in the presence of dyspnoea in a patient with severe obesity, the PNDS recommends not laying the patient flat, investigating heart failure, pulmonary embolism and respiratory failure due to hypoventilation, and measuring blood gases; benzodiazepines and other respiratory depressants should be avoided, and during hospital admission access to food should be controlled, physical activity maintained and the caregiver involved [19].

7.8 Immunodeficiency by unmasking

When the deletion removes the only functional allele of CORO1A (pathogenic variant on the other chromosome), the clinical presentation is that of a severe combined T−B+NK+ immunodeficiency, with recurrent infections, including severe post-vaccination varicella at 13 months in the patient described, and the management is that of severe combined immunodeficiencies [46]. This scenario is rare, but exemplifies the need to consider recessive diseases whose genes lie within the interval when the phenotype exceeds that expected [11].

7.9 Clinical trials, research and recent developments

Interpretation of these studies requires caution. The basket trial is open-label, short-term, and has no control group, and the average weight loss of approximately 2% in the 16p11.2 cohort is lower than that observed in the approved indications for setmelanotide; the randomised, placebo-controlled EMANATE showed no difference in the SH2B1 substudy, which, until full publication, should be treated as the topline result of a sponsor press release and not as peer-reviewed evidence [22, 97]. The two trials test different populations (proximal deletion in the broad sense in the basket trial; SH2B1, including distal deletion, in EMANATE), so the result should not be transferred from one to the other. Comparison between drugs from these studies and the liraglutide series is not valid because designs, populations and outcomes differ [91, 92].

Data from the last 12 months include the EMANATE press release (March 2026), the re-evaluation of the proximal region by ClinGen (March 2026), the study of genetic modifiers and ascertainment published in Cell (October 2025), a Chinese prenatal series of 13 fetuses (June 2026) and a pre-publication meta-analysis, not yet peer reviewed, of 1.45 million individuals that showed mirror and context-dependent effects of 16p11.2 CNVs on height and BMI [4, 22, 50, 104, 105]. Preclinical research has identified targets such as TAOK2 (whose reintroduction attenuates deficits in the deletion mouse) and the primary cilium, without clinical translation to date [38, 40].

8. Reproductive Options and Family Counselling

8.1 Origin of CNV and risk for family members

The proximal deletion is de novo in most probands, but the proportion varies with the cohort: 93% of probands with parents tested according to GeneReviews, 70.2% (33/47) in the laboratory cases of Rosenfeld and colleagues, 74.5% (35/47) in the Dutch series, and 64% (92/145, including two mosaics) in the Zufferey cohort, which brought together probands from the European consortium (25 de novo out of 53 with parental study), Simons VIP (27/34) and the literature [1, 2, 6, 11]. The difference probably reflects the method of ascertainment: cohorts recruiting families with transmission increase the inherited proportion, and cohorts of probands with a more marked phenotype increase the de novo proportion. In the proximal duplication, about 25% are de novo; in the 2010 Rosenfeld laboratory series, of the 19 duplications with parental study 5 were de novo, 9 maternal and 5 paternal [2, 106]. In the distal deletion, only 2 of 8 were de novo in the Dutch series [2].

Parental bias is discussed in the sources with different conclusions. Rosenfeld and colleagues observed, in inherited proximal deletions, a maternal transmission bias (14 of 68 carrier mothers versus 0 of 38 fathers; p=0.0018) [11]; Duyzend and colleagues found a marked maternal bias in the origin of de novo deletions (89.4%), but not in inherited CNVs [34]; GeneReviews states that no parental origin bias has been described, and Egolf and colleagues observed no bias in four trios [1, 69]. These observations refer to distinct phenomena (meiotic origin of the de novo event versus transmission of an already existing CNV) and do not change the risk of recurrence, but must be explained precisely when the family asks about the “origin” of the deletion.

8.2 Penetrance and counselling regarding a susceptibility CNV

The Oxford manual places these CNVs among the “loci of predisposition or neurosusceptibility”, found most frequently in children with neurodevelopmental disorders but sometimes inherited from apparently normal parents, and highlights that there is no consensus on cascade testing or prenatal diagnosis, due to the uncertainty of the prognosis [11]. The penetrance estimates derived by Rosenfeld and colleagues are an aid to counselling:

Source: Table 5.5 from the Oxford Desk Reference, reproduced from Rosenfeld and colleagues (2013), with original coordinates in hg18 [11, 12].

The “penetrance” of these estimates is the probability of a carrier having a clinically recognised abnormal phenotype (congenital anomalies, developmental delay or intellectual impairment), assuming a baseline risk of about 5%; it is not the risk of ASD, schizophrenia or obesity, nor does it describe subclinical effects [12]. In carriers from the general population, CNVs associated with schizophrenia and other neurodevelopmental disorders are associated with modestly lower cognitive performance and lower educational attainment, occupational status and income, even without a neuropsychiatric diagnosis [55, 107–109]. Smith frames these CNVs in the multifactorial model, in which they interact with other genetic and environmental factors, and notes that empirical risks continue to be the basis of counselling [68]. In practice, Moreno-De-Luca's data allow parents to be told that, in a de novo deletion, the child's cognitive and social performance tends to correlate with the family profile, shifted by approximately 1 to 2 SD [49].

8.3 Prenatal and pre-implantation diagnosis

Once CNV is identified in the family, prenatal diagnosis by chorionic villus sampling or amniocentesis and pre-implantation genetic testing are possible, but the result does not allow reliably predicting the phenotype, although the majority of deletion carriers have language delay and some cognitive limitation [1]. The Oxford manual recommends taking time and care with consent when the carrier parent has learning difficulties, and emphasises caution in CNVs of variable penetrance [11]. The ideal time to discuss risks and options is before pregnancy, and counselling should be offered to young adults who are carriers or at risk [1, 18].

Prenatal detection occurs mainly by microarray performed due to ultrasound abnormalities. The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine recommend microarray in pregnancies with one or more major structural anomalies undergoing invasive diagnosis [110]. In a series of 20,884 amniotic fluid samples, 20 fetuses (0.10%) had 16p11.2 CNVs: 10 BP4–BP5 deletions, 5 BP2–BP3 deletions, and 5 BP4–BP5 duplications; spinal or rib anomalies and increased nuchal translucency were the most common structural and non-structural findings in BP4–BP5 deletions, BP2–BP3 deletion appeared to be associated with fetal growth restriction and single umbilical artery, and no duplication had ultrasound changes; 11 pregnancies involving a deletion were terminated [74]. In a 2026 Chinese series of 13 fetuses, 5 of 12 CNVs with parental study were de novo and 7 inherited from a phenotypically normal parent; the main ultrasound findings were cardiovascular, vertebral and increased translucency [104]. The 2023 review also mentions congenital heart disease and congenital diaphragmatic hernia as occasional findings that lead to prenatal diagnosis [18].

The reporting of CNVs with incomplete penetrance in the prenatal setting is heterogeneous. The Oxford manual states that some laboratories do not routinely report, prenatally, syndromes with substantial incomplete penetrance, as the result is uncertain and unlikely to explain the ultrasound findings [11]. In France, the AchroPuce consortium defined a list of 17 CNVs of incomplete penetrance and variable expressivity; in a survey of 121 professionals, 76% (prenatal diagnosis) and 84% (fetal pathology) were in favour of communicating these results, with multidisciplinary consultation as the central point before the family study [111]. Pre-test counselling should therefore explain that the result may reveal CNVs of probabilistic significance [79]. In France, according to the PNDS for obesities of rare cause, a request for prenatal or preimplantation diagnosis made by a couple after a genetics clinic consultation is examined at a multidisciplinary meeting of a prenatal diagnosis centre, and the law only allows it for conditions of particular severity without curative treatment at the time of diagnosis, a framework that, for a CNV of incomplete penetrance, makes the decision case by case [19].

8.4 Reproduction and contraception in carriers

The 2023 review recommends discussing sexuality, contraception and referral for reproductive counselling with adolescent and adult carriers, and mentions the possibility of earlier menarche and puberty [18]. Anti-obesity drugs should be discontinued when pregnancy is recognised, and semaglutide at least 2 months before a planned pregnancy [89, 94]. For women with obesity of rare cause, the French PNDS recommends a preconception consultation (folic acid, vaccines and serology, assessment of diabetes, hypertension, sleep apnoea, thromboembolic risk and the liver, switching chronic treatments to non-teratogenic drugs, and genetic counselling on transmission), assessment of the capacity to understand the challenges of pregnancy when there is a neurodevelopmental disorder, screening for gestational diabetes by fasting glucose in early pregnancy and, if negative, a 75 g oral glucose test between 24 and 28 weeks, follow-up in a maternity unit of at least level 2, early anaesthetic assessment (intubation, epidural if there is scoliosis, venous access) and thromboembolic prophylaxis [19]. Regarding contraception, it notes that a BMI ≥30 kg/m² does not contraindicate any method according to the HAS, but that obese women taking a combined oral contraceptive have a venous thromboembolic risk about 24 times that of lean non-users, so the choice is individual; with ID, hormonal contraception can be used to reduce or suppress menstruation [19].

9. Special Considerations: Population Diversity and Epidemiology

9.1 Frequency in the population and in clinical cohorts

The proximal deletion has a frequency of about 1 in 2000 in the general population [1, 24]. In the Norwegian MoBa cohort, with 12,252 mother-father-child trios, the prevalence in newborns was around 1:2000, higher than previous estimates, and the set of 26 recurrent neurodevelopmental CNVs reached 0.48% of live births, with around a third de novo [10]. Orphanet reports a point prevalence of 1–5 per 10,000 for the proximal deletion, validated for Europe and the United States [9]. In Iceland, the deletion was found in 2 of 18,834 unscreened controls [27]; in the Estonian biobank, CNV carriers of known syndromes not clinically selected showed similar phenotypes to the clinical cohorts, including cognitive and psychiatric problems, epilepsy, obesity and malformations [55]. Frequencies in clinical cohorts are not prevalences: 0.28% of patients referred for microarray in the European and Simons VIP consortia, 0.6% of samples subjected to clinical aCGH in a series (deletions and duplications), 0.78% of 9773 individuals referred to a diagnostic laboratory (deletions and duplications), about 0.5% of ASD cohorts, and about 1% of autism cases in the original estimate [6, 27, 82, 83, 106].

For proximal duplication, GeneReviews indicates 0.05–0.09% of the population, and the Dutch series cites about 1:2500; the distal deletion has been estimated at around 1:4100 and the distal duplication at around 1:1500, with a combined prevalence of proximal and distal CNVs of around 1 in 600 [1, 2]. Orphanet classifies proximal duplication as having a prevalence of less than 1/1,000,000, based on published case counts; this value conflicts with the population data above and should not be used as a frequency estimate; for the distal deletion, the prevalence is reported as unknown [9].

9.2 Sex, ascertainment and modifiers

In the Zufferey cohort, probands with the deletion were mostly boys (85 European carriers: 56 males and 28 females), with no difference in the general population, which suggests ascertainment bias, and sex did not significantly modify IQ or other traits [6]. In duplication, Jacquemont and colleagues observed a trend towards greater severity in boys and fewer male carriers among cases identified outside the medical context [14]. The genetic background and the method of ascertainment influence expressivity, as shown by modifier studies and the 2025 analysis [34, 50].

9.3 Data by region and founder populations

Available data come mainly from the United States (Simons VIP, clinical laboratories), Europe (European 16p11.2 consortium with French, Swiss and other centres; Netherlands; United Kingdom; Norway; Estonia; Iceland) and China and Japan in the TBX6 studies [2, 6, 10, 27, 41, 42, 55]. Iceland and the Ashkenazi population, populations with a founder effect, respectively contributed to the discovery of the association with autism and to the identification of the distal deletion as a risk factor for schizophrenia, but the sources consulted do not describe a founder effect for the 16p11.2 deletion, which mainly arises de novo through non-allelic recombination [27, 75]. The hypomorphic haplotype of TBX6 is common; the compound inheritance model was demonstrated in Chinese patients (11%) and replicated in Japanese (9 of 94), and the proportion attributable in other populations was not measured in the sources consulted [41, 42]. Analysis of neuroblastoma, conducted in multiethnic cohorts, maintained the association when restricted to European ancestry [69].

In Portugal, the sources consulted include the case published by the Centro Hospitalar e Universitário de Coimbra, described in section 10 [70]. No Brazilian data were found in the sources consulted (manuals, GeneReviews, GeneGuidance and main articles), which does not demonstrate its non-existence; the search did not include targeted geographic searches.

9.4 Reference networks and patient associations

In Europe, the relevant European reference network is ERN ITHACA, the European reference network for rare malformation syndromes and rare disorders of intellectual development and neurodevelopment [23]. Associations and registries with specific information include Unique (Rare Chromosome Disorder Support Group, UK), which publishes family guides on 16p11.2 microdeletions and duplications in several languages, Simons Searchlight (international registry with participation in English, Spanish, French and Dutch), Chromosome Disorder Outreach and the 16p11.2 Genetic Foundation [1, 18, 103, 112]. In France, obesity of rare cause is managed by the PRADORT reference centre (Prader-Willi syndrome and other rare obesities with eating-behaviour disorders), part of the DéfiScience network, coordinated at the CHU de Toulouse, with constituent sites at the Pitié-Salpêtrière (Paris) and the Hôpital Marin d'Hendaye and 20 competence centres, working with the 37 specialised obesity centres, which provide third-level care, and with the competence centres «Déficiences intellectuelles de causes rares» of the same network [19]. The PNDS also provides for the équipes relais handicaps rares, which link families, medico-social services and hospitals, the file with the Maison Départementale des Personnes Handicapées (MDPH) with a global support plan in breakdown situations, assessment, crisis or respite stays in specialised rehabilitation centres (Hendaye for adults, OCSYHTAN in Ramonville Saint-Agne for children), dedicated consultations for examinations in people with disabilities, and teleconsultation [19].

10. Illustrative Clinical Case

10.1 Late diagnosis in an adult with severe obesity (Coimbra, Portugal)

Ventura and colleagues, from the Centro Hospitalar e Universitário de Coimbra, described a 25-year-old man referred to an endocrinology consultation due to class III obesity [70]. He reported significant weight gain over the previous 10 years, was taking levothyroxine 50 µg/day for hypothyroidism with no defined aetiology, and reported decreased libido, polydipsia greater than 5 litres/day and polyuria; the mother described difficulties with social interaction since childhood. The examination showed a BMI of 46 kg/m², abdominal circumference of 132 cm, loss of facial hair, reduced testicular volume (12 and 10 mL), macrocephaly, broad forehead, wide and prominent nasal root, anteverted nares and mild brachydactyly of the fourth and fifth fingers [70].

Endocrine evaluation revealed hypogonadotropic hypogonadism (FSH <0.3 mIU/mL, LH <0.1 mIU/mL, total testosterone 0.4 ng/mL), subnormal adrenal reserve in the stimulation test with 250 µg of ACTH (peak cortisol of 19 µg/dL), and central diabetes insipidus confirmed by water deprivation test (urine output of approximately 8500 mL/24 h, urinary osmolality of 104 mOsm/kg) [70]. Sellar MRI showed two lesions, suprasellar (13 mm) and pineal (9 mm), with homogeneous enhancement, suggestive of germinoma (Figure 1 of the original article); serum alpha-fetoprotein and β-hCG were normal, and cerebrospinal fluid β-hCG was slightly elevated (8.8 mIU/mL) [70]. Due to the association of obesity and social difficulties, a microarray was requested, which, with a 46,XY karyotype, identified arr[hg19] 16p11.2(29,592,783–30,197,341)x1, a 604 kb deletion compatible with the BP4–BP5 recurrent deletion (Figure 2 of the original article) [70]. Pterional craniotomy biopsy confirmed germinoma (PLAP, CD117, OCT4 and SALL4 positive) [70].

The patient started testosterone 125 mg every 4 weeks, hydrocortisone 10 mg upon awakening and 5 mg in the afternoon and desmopressin 0.06 mg/day, with levothyroxine titration up to 175 µg/day, and received radiotherapy of the ventricular system (24 Gy in 15 fractions) followed by tumour boost (16 Gy in 10 fractions), which was well tolerated [70]. Three months later, the pineal lesion had disappeared and the suprasellar lesion was reduced to the pituitary stalk (Figure 3 of the original article), but the pituitary deficits remained, with low IGF-1 (62 ng/mL) and adrenal insufficiency that required an increase in hydrocortisone [70]. The doses described are those in the report and only serve to contextualise it; they do not constitute a recommendation for the 16p11.2 deletion.

The case illustrates three points. First, carriers of the deletion can reach adulthood without a diagnosis, and the combination of obesity, macrocephaly, and history of social difficulties should prompt microarray at any age [6, 70]. Second, a carrier's obesity should not be automatically attributed to CNV: in this patient, hypogonadism, adrenal insufficiency and diabetes insipidus pointed to a hypothalamic-pituitary lesion, which required its own investigation. Third, the authors consider the association between 16p11.2 deletion and germinoma to be a new hypothesis, based on a single patient; there is no basis for proposing screening for germ cell tumours in carriers [1, 70].

10.2 Paroxysmal kinesigenic dyskinesia with normal PRRT2 sequencing

Termsarasab and colleagues reported a 12-year-old boy, with characteristics of Asperger syndrome and mild language delay that required speech and occupational therapy at the age of 4–5 years, who at the age of 10.5 years began episodes of arm and trunk dystonia lasting 5 to 10 seconds, sometimes with arching of the back, documented on video by the family [47]. Sequencing of the coding regions and splice junctions of PRRT2 was normal, but aCGH detected a 533.9 kb de novo deletion, arr 16p11.2(29,564,185–30,098,069)x1 in hg18, which included PRRT2, KIF22, ALDOA and TBX6, confirmed by FISH (Figure 1 of the original article); a paternal duplication of 170.5 kb was also identified in 21q22.11–q22.12 [47]. Carbamazepine up to 250 mg/day improved the frequency and severity of episodes but worsened anxiety; when reintroduced up to 200 mg/day, the episodes improved again, but leucopenia appeared (2800/µL) [47]. In the review of the five cases published at that time of dyskinesia with proximal deletion, the age of onset varied from childhood to 10.5 years, three patients had infantile seizures and all had some delay, especially in language [47].

The case reinforces that sequencing of PRRT2 does not detect the deletion, that the coexistence of paroxysmal dyskinesia with language delay or ASD should lead to microarray, and that treatment with carbamazepine, although effective, requires surveillance for haematological adverse effects, according to the label [47, 87]. The rarity of dyskinesia among carriers, documented in the Dutch series, shows that the deletion of PRRT2 is not sufficient, by itself, to produce the paroxysmal phenotype [37].

11. Prognosis and Long-Term Follow-Up

11.1 Prognosis

There is no life expectancy data for carriers of 16p11.2 CNVs in the sources consulted. The natural history is dominated, in childhood, by neurodevelopmental disorders and, in adulthood, by obesity and its comorbidities, which can be aggravated by psychotropic drugs [1]. Associated epilepsy has, as a rule, a good prognosis, with control and remission in the majority [58]. School-age children may show a trajectory of progressively falling behind their peers, which justifies regular cognitive reassessment [59]. In adulthood, biobank data show that undiagnosed carriers accumulate effects on health (diabetes, hypertension, obesity, kidney function) and on educational attainment, occupational status and income, even when they have escaped neurodevelopmental diagnoses in childhood [63, 108]. These biobank estimates describe carriers with a milder phenotype and do not directly apply to patients diagnosed in a clinical setting.

11.2 Surveillance

11.3 Transition to adulthood

The 2023 review recommends preparing for the transition to adult care, discussing financial planning and, when the level of functioning warrants it, legal protection measures before the age of 18, guidance on sexuality, contraception and reproduction, routine age-appropriate cancer screening and maintenance of metabolic surveillance [18]. In the duplication, surveillance should include underweight and food selectivity in childhood and mental health in adults, taking into account the risk of schizophrenia [14, 15]. In the distal deletion, early obesity and the risk of difficult-to-control type 2 diabetes justify metabolic surveillance from an early age [2, 52]. The French PNDS for obesities of rare cause recommends announcing and preparing the transition from 15–16 years, with an adult coordinator identified early, a multidisciplinary transition consultation or meeting between the paediatric and adult teams, a transition booklet owned by the patient and a prior visit to the adult service, because adolescence and transition are periods of worsening weight, eating behaviour and behavioural disorders [19].

12. Summary and Concluding Remarks

The proximal 16p11.2 BP4–BP5 deletion is a recurrent ~593 kb CNV, mediated by non-allelic homologous recombination, present in approximately 1 in 2000 people and responsible for a fraction of neurodevelopmental disorders and ASD; diagnosis depends on a microarray or exome/genome with validated CNV calling rather than clinical recognition [1, 10]. The phenotype combines developmental delay, apraxia of speech, language disorder, psychiatric disorders, coordination impairment, epilepsy with a good prognosis, macrocephaly, vertebral anomalies and progressive obesity with hyperphagia, and the average IQ shifts about 2 SDs in relation to the family, with great variability [1, 6, 49]. Reciprocal duplication has similar average cognitive effect but greater variance, increased risk of schizophrenia and mirror growth phenotypes (underweight, microcephaly) [13–15]. The distal BP2–BP3 deletion, which includes SH2B1, is a distinct entity, with earlier and more severe obesity, insulin resistance, and diabetes, and should not be confused with the proximal deletion in reporting or counselling [2, 16, 52].

Individual genes of the interval explain partial phenotypes: PRRT2 the paroxysmal phenotypes, TBX6 the congenital scoliosis and part of the renal anomalies by compound inheritance with a hypomorphic haplotype, KCTD13, TAOK2 and other genes the brain size and neurodevelopment, and CORO1A the risk of unmasking a recessive immunodeficiency [1, 36, 41, 43, 46]. Incomplete penetrance and the effect of family background make counselling probabilistic, with transmission risks of 50% for carriers, recurrence risk of around 1% when the deletion is de novo and estimated penetrances for abnormal phenotype between 11% and 62%, depending on the CNV [1, 11, 12].

Management is based on early intervention in development and speech, standard treatment of epilepsy, orthopaedic, auditory and neurological surveillance and, above all, early prevention of obesity with portion control and avoidance of obesogenic psychotropic drugs [1, 18]. No drug has a specific indication; GLP-1 analogues can be used in general obesity indications in the prescribing information, with evidence limited to case series, and setmelanotide demonstrated no benefit in the SH2B1 substudy of the phase 3 EMANATE trial, according to the March 2026 press release [22, 91]. In prenatal diagnosis, vertebral anomalies and increased nuchal translucency are the most frequent findings of the deletion, and reporting these CNVs of incomplete penetrance requires prior counselling and multidisciplinary discussion [74, 111]. In Europe, ERN ITHACA and patient associations such as Unique and Simons Searchlight are the reference resources [23, 103, 112].

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