Beck-Fahrner Syndrome (TET3)

A neurodevelopmental disorder caused by reduced activity of the TET3 dioxygenase, the enzyme that initiates active DNA demethylation; the first Mendelian disorder described in the machinery that removes DNA methylation, with global developmental delay or intellectual disability, hypotonia, autistic features, epilepsy, growth differences and non-specific facial dysmorphism, transmitted by monoallelic variants (mostly de novo) or by biallelic hypomorphic variants.

Literature and regulatory information updated: 28 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Historical overview

The first association between TET3 and human disease came from a candidate gene study for autosomal recessive intellectual disability published by Santos-Cortez and colleagues in 2018, in which a consanguineous Pakistani family with three affected siblings was homozygous for a TET3 missense variant [20]. That family became “family 3” of the series that, two years later, defined the clinical entity [11]. In February 2020, David B. Beck, Jill A. Fahrner and colleagues at Johns Hopkins University described in the American Journal of Human Genetics 11 individuals from 8 families with global developmental delay or intellectual disability, hypotonia, autistic features, movement disorders, growth differences and facial dysmorphism, carrying monoallelic or biallelic TET3 variants [11]. The initial proband, a girl with generalised overgrowth, macrocephaly and a facial appearance reminiscent of Sotos syndrome, had had negative targeted tests for NSD1, NFIX, for Beckwith-Wiedemann syndrome and on array comparative genomic hybridisation (array-CGH); the diagnosis came from a research trio exome, and the remaining patients were gathered through collaborations and the GeneMatcher platform [11]. The paper presented the condition as the first Mendelian disorder of the DNA demethylation machinery, at a time when disorders of the methylation “writers” (DNMT3B in immunodeficiency, centromeric instability and facial anomalies syndrome type 1, recessive; DNMT3A in Tatton-Brown-Rahman syndrome, dominant) and “readers” (MECP2 in Rett syndrome) were known, but no disease consistently linked to the process that removes methylation [11].

In November 2021, Levy, Beck, Sadikovic, Fahrner and colleagues described a whole-blood DNA hypermethylation episignature, added 8 patients from 5 families and proposed the eponym and the mnemonic BEFAHRS [3, 21]. There followed reports of two Japanese families, one with a de novo variant and the other with compound heterozygous variants [22], and of a Turkish boy with a de novo loss-of-function variant and electrical status epilepticus during slow-wave sleep (ESES) [23]. The GeneReviews chapter, published in May 2023 by Fahrner herself, brought together 28 individuals from 16 families described in five publications and remains the only management synthesis [1]. Later reports broadened the phenotype: an Italian woman diagnosed at 31 years of age, with drug-resistant epilepsy and ESES, macrocephaly and tall stature [12]; a Canadian boy with chorioretinal and iris colobomas whose variant was reclassified by the episignature [13]; a pair of Chinese monozygotic twins with a de novo missense variant [14]; and a Chinese infant with a de novo frameshift variant [15].

1.2. Place among the Mendelian disorders of the epigenetic machinery

The concept of Mendelian disorders of the epigenetic machinery (MDEM) was proposed by Fahrner and Bjornsson in 2014 to designate disorders caused by germline variants in genes encoding components of the epigenetic or chromatin-modifying machinery [10]. Chromatin is DNA together with its associated histones, and epigenetic marks are modifications of this chromatin, on DNA or on histones, that alter gene expression without changing the sequence [1]. MDEM genes are classified by the function of the proteins they encode: writers place marks, erasers remove them, readers interpret them and remodellers alter chromatin architecture [24, 25]. Most of these disorders are autosomal dominant, result from haploinsufficiency and share global developmental delay, intellectual disability, growth differences (overgrowth or growth deficiency) and characteristic craniofacial features [10, 11]. Beck-Fahrner syndrome belongs to the DNA methylation erasers subgroup and overlaps clinically with the overgrowth–intellectual disability syndromes, a group in which variants of the epigenetic machinery account for about 45% of cases according to the Tatton-Brown study cited by Beck and colleagues [11].

1.3. Nomenclature

The names in use are Beck-Fahrner syndrome, BEFAHRS, TET3-BEFAHRS and TET3 deficiency [1, 3]. OMIM assigns the phenotype number 618798 and the gene number 613555, and brings together the monoallelic and biallelic forms in a single phenotype entry, with both modes of inheritance recorded, precisely because some heterozygous carriers in the recessive families have a milder picture of the same type [1, 4, 9]. In the gene entry, TET3 also appears under the historical names TET oncogene family, member 3 and KIAA0401 [4]. Orphanet uses a descriptive name as its preferred term, intellectual disability–facial dysmorphism–joint hypermobility–hearing loss syndrome (ORPHA:684216), and keeps BEFAHRS, Beck-Fahrner syndrome, TET3 deficiency and TET3-related Beck-Fahrner syndrome as synonyms [2]. The eponym honours the first author and the senior author of the founding paper [3].

1.4. Definition and scope of the article

Beck-Fahrner syndrome is defined as the neurodevelopmental disorder associated with a heterozygous pathogenic or likely pathogenic TET3 variant, or with biallelic hypomorphic variants, in an individual with compatible clinical findings, with no published consensus clinical criteria [1]. No other phenotypes associated with germline TET3 variants are known [1]. Two neighbouring entities are covered only in the differential diagnosis: the 2p13.2-p11.2 contiguous deletion syndrome, which includes TET3 among several genes [26], and the developmental disorder caused by biallelic loss of function of PROSER1, a protein that regulates the TET enzymes [27]. Tatton-Brown-Rahman, Sotos, Kabuki and fragile X syndromes and the SETD2-related disorder are part of the differential.

2. Molecular Genetics and Pathophysiology

2.1. The TET3 gene and protein

TET3 lies at 2p13.1 and encodes the methylcytosine dioxygenase TET3, one of the three members of the TET (ten-eleven translocation) family, together with TET1 and TET2 [1, 11]. The MANE Select transcript is NM_001287491.2 (ENST00000409262.8), with the coding sequence between positions 673 and 6060 of the mRNA, and it encodes isoform 1, NP_001274420.1, of 1795 amino acids, which matches the canonical UniProt sequence O43151 [6–8]. In NP_001274420.1 numbering, the protein has a CXXC DNA-binding domain at amino acids 46–102 and a catalytic dioxygenase domain at amino acids 773–1776, which contains a cysteine-rich insert (amino acids 825–1012) and the double-stranded β-helix (DSBH) core, split into two segments (amino acids 1012–1159 and 1636–1719) by a low-complexity insert [11, 14]. The first data on the gene came from a partial brain cDNA clone (KIAA0401), described in 1997, expressed mainly in the brain, placenta, lung and thymus; in 2009 the protein annotation predicted 1660 amino acids, the length of an old model that does not correspond to the current MANE isoform, and expression was ubiquitous, highest in haematopoietic cells of the myeloid and monocytic lineages [4]. The catalytically inactive mutant used as an experimental reference alters the iron-binding motif (p.His1077Tyr/Asp1079Ala, designated HxD) [11]. TET3 binds preferentially to CpG dinucleotides, selectively occupies promoters of developmental genes and recruits the O-GlcNAc transferase OGT to CpG-rich transcription start sites of active genes, where it promotes GlcNAcylation of histone H2B [5]. TET3 has a pLI (probability of loss-of-function intolerance) of 1 in the gnomAD (Genome Aggregation Database) population database (observed/expected ratio for loss of function 0.02), indicating almost complete intolerance to loss-of-function variants [11].

2.2. Active DNA demethylation

The TET enzymes sequentially oxidise 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), then to 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) [11, 28]. 5fC and 5caC are removed passively, by dilution during replication, or actively by thymine DNA glycosylase (TDG), with final replacement by unmethylated cytosine, which completes demethylation [1, 11]. 5hmC is particularly abundant in the brain and may have a regulatory function of its own [11]. Tet3 is highly expressed in oocytes, zygotes and neurons; TET3 rapidly demethylates the genome of the paternal pronucleus after fertilisation [5, 11]. In the mouse, Tet3 ablation is lethal in the embryonic period, haploinsufficiency produces sub-Mendelian ratios and partial neonatal lethality, and inhibition or depletion in differentiated neurons affects synaptic function [11]. Maternal TET3 also matters: in female mice with conditional germline deletion of Tet3, conversion of 5mC to 5hmC in the paternal genome of the zygote did not occur, demethylation of paternal Oct4 and Nanog was delayed, fecundity was markedly reduced and offspring deprived of maternal TET3 had more developmental failures [4]. Simultaneous inactivation of the three Tet genes in the mouse prevents gastrulation, through hypermethylation and silencing of Lefty1 and Lefty2 with Nodal pathway hyperactivity, a defect that inactivation of Dnmt3a and Dnmt3b largely corrects; a point mutation that abolishes only the dioxygenase activity reproduces the picture, which identifies catalytic function as the essential component [4]. Outside the nervous system, TET3 is the most highly expressed family member in late human erythropoiesis, and its depletion in vitro impairs erythroblast enucleation; the clinical sources consulted do not describe haematological abnormalities in patients [1, 4]. Mutant mouse models have impaired motor coordination, anxiety-like behaviours and learning and memory deficits, according to the review by Mei and colleagues [14].

2.3. Disease mechanism

The mechanism is loss of function [1]. In an overexpression assay in HEK293 cells with 5hmC quantification by dot blot, all recessive variants tested, except p.Arg752Cys, reduced 5hmC production relative to wild type, which characterises them as hypomorphic; the monoallelic variants were not tested because the assay does not detect small reductions in the presence of the wild-type allele [11]. Beck and colleagues proposed a threshold model: the phenotype arises when total TET3 activity falls below a critical level, whether through a heterozygous loss-of-function variant, a heterozygous missense variant, or two hypomorphic missense variants [11]. Nonsense and frameshift variants have only been observed in the heterozygous state, which suggests that some residual activity is required for viability, consistent with the lethality of the null mouse model [11]. The authors did not exclude a dominant-negative or activating effect of some monoallelic variants, because p.(Gln1695Ter) and p.(His1660ProfsTer52) lie in the last exon and may escape nonsense-mediated mRNA decay [11].

The measurable molecular consequence is a hypermethylated genome-wide methylation profile in whole blood [3]. Mean global methylation shifts slightly towards higher values, with a greater effect in biallelic patients (median beta value 0.787 in controls, 0.789 in monoallelic and 0.801 in biallelic patients) [3]. The 50 differentially methylated regions identified were all hypermethylated; 35 of the 39 associated coding transcripts are expressed in the brain, and the genes in these regions show increased expression in excitatory and inhibitory fetal cortical neurons [3]. The working hypothesis is that altered expression of neurodevelopmental target genes leads to the manifestations; epigenetic marks differ between tissues, and it is not known whether the changes in blood reflect those in the brain [1, 3]. There is no accumulated metabolite and no plasma enzyme assay [5]. TET3 interacts biochemically with proteins encoded by other overgrowth–intellectual disability syndrome genes (NSD proteins, SETD2, histone H1.4 encoded by H1-4/HIST1H1E and SUZ12), which offers an explanation for the phenotypic overlap [11].

2.4. Pattern of inheritance: the two positions

The sources differ in how they record inheritance, and both positions have documentary support. The founding paper described autosomal dominant and autosomal recessive forms: five families with monoallelic variants (four de novo and one with father-to-son transmission) and three families with biallelic variants (two compound heterozygous and one homozygous in a context of consanguinity) [11]. OMIM and Orphanet record both modes of inheritance [2, 9]. The Japanese series added a family with inherited biallelic variants, in which neither parent was described as affected, although it is unclear whether they were fully assessed [1, 22].

GeneReviews concludes that the disorder is autosomal dominant with variable expressivity and that hypomorphic alleles may mimic recessive inheritance [1]. Three observations support this reading. First, in the biallelic families the heterozygous parents often had mild features: learning difficulties with individualised education plans, attention deficit hyperactivity disorder (ADHD), seizures in childhood, severe anxiety, depression or borderline psychosis [11]. Second, on methylation analysis, the parents carrying the variants p.Val1089Met (46-year-old mother), p.Val908Leu (64-year-old father) and p.Ala1076Thr (28-year-old mother) had a pathogenic monoallelic profile [3]. Third, proband 1-II-1, initially described as compound heterozygous for p.Arg752Cys and p.Val1089Met, proved to be “functionally monoallelic”: p.Arg752Cys had normal activity in the enzyme assay and an intermediate methylation profile, close to controls, in the carrier father, and was reclassified as likely benign, whereas the mother carrying p.Val1089Met had anxiety, depression, possible ADHD and a monoallelic profile [3, 11]. Because the episignature is dose-dependent and separates biallelic patients, monoallelic patients and controls, biallelic individuals represent the severe end of a continuous spectrum of reduced TET3 activity [3]. In clinical practice, the two readings agree on the risk to the offspring of a heterozygous patient (50%) and differ on the expected phenotype in parents carrying a hypomorphic allele, which should be actively sought.

2.5. Variant spectrum

All missense variants in the founding series, except p.Arg752Cys, lie in the catalytic domain, at residues conserved across species and, in many cases, across TET1, TET2 and TET3; projected onto the TET2 crystal structure, p.Val1089Met and p.Phe1072Cys lie next to the residue that forms a hydrogen bond with the cytosine of 5hmC [11]. Loss-of-function variants are distributed along the gene, including the last exon [3, 11]. In the scheme by Foti and colleagues, adapted from Sager, 11 missense, 5 nonsense and 3 frameshift variants had been described up to 2024 [12]. No founder variants have been identified; homozygosity for p.Val908Leu occurred in a consanguineous family [11, 20]. In ClinVar, on 28 October 2026, TET3 had 624 records, 70 classified as pathogenic or likely pathogenic and 400 classified as variants of uncertain significance (VUS) [29].

The following table brings together the variants published in the sources read, normalised to the MANE transcript. The c. numbering of NM_001287491.1, used in the papers by Beck, Levy, Seyama and Foti, is identical to that of NM_001287491.2 [6].

2.6. Transcripts and historical nomenclature

There is an alternative transcript, NM_001366022.1 (isoform 2, NP_001352951.1, 1702 amino acids), whose numbering is shifted by 279 nucleotides and 93 amino acids relative to MANE [6, 7]. The variant reported by Sager and colleagues, published on that transcript as c.1594C>T p.(Arg532Ter), corresponds in MANE to c.1873C>T p.(Arg625Ter), at NC_000002.12:g.74047790C>T [6, 23]. Likewise, MANE p.(Arg752Cys) corresponds to p.(Arg659Cys) on the alternative transcript, and p.(His1660ProfsTer52) to p.(His1567ProfsTer52) [6]. The notations c.1215delA and c.2036dupC in the original papers are written, under current Human Genome Variation Society (HGVS) rules, as c.1215del and c.2036dup, and the insertion c.2811_2812insAGAC published in Chinese corresponds to the duplication c.2809_2812dup [6]. A recent paper assigns the protein 1776 amino acids and cites a non-canonical UniProt identifier; the length of the MANE isoform is 1795 amino acids, and 1776 coincides with the boundary of the catalytic domain [8, 11, 14].

2.7. Genotype-phenotype correlations

No genotype-phenotype correlation has been confirmed [1]. Three trends have been described in small numbers. In the founding series, macrocephaly was concentrated in the monoallelic patients (families 4, 5 and 6) and in proband 1-II-1, who later proved to be functionally monoallelic, whereas the two homozygous consanguineous siblings had microcephaly [11]. Beck and colleagues suggested an inverse relationship between residual activity and severity, with mildly affected carrier parents [11]. Levy and colleagues noted that two of the three monoallelic missense variants described in the cysteine-rich region (p.Arg911Gln and, in the carrier parent, p.Val908Leu) were associated with psychiatric symptoms with onset in adolescence or adulthood, without this being generalisable [3]. In the initial series all monoallelic probands were male and almost all biallelic probands were female, an imbalance the authors attributed possibly to chance [11].

2.8. Allelic disorders, additional variants and modifiers

No germline allelic disorders of TET3 are known [1]. Unlike TET2, TET3 has not emerged as a gene with somatic mutations in myeloid neoplasms: in a study of 96 patients with myeloproliferative neoplasms no somatic TET3 variants were found [4]. Four affected individuals also had copy number variants (for example, a paternal 16p11.2 duplication in individual 8-II-1 and a maternal 16q22.1q22.2 duplication in 2-II-1), and one affected individual had biallelic variants in a recessive disease gene that does not explain the whole phenotype; the contribution of these findings remains uncertain [1, 11]. The assignment of inheritance in the founding series was based on exome sequencing, which does not exclude non-coding variants in trans in the cases considered de novo [11]. Contiguous 2p13.2-p11.2 deletions include TET3, and a 2026 study proposes that loss of TET3 and CCT7 aggravates the phenotype of that multigene deletion syndrome [26]. The PROSER1 protein forms, with TET, OGT and the DBHS proteins, the complexes designated TOPD and regulates demethylation; its biallelic loss of function causes a developmental disorder with malformations, which places PROSER1 in the same pathway [27].

3. Clinical Spectrum and Manifestations by System

3.1. Cohorts and limits of the data

Clinical knowledge rests on small series and case reports. The founding series brought together 11 individuals from 8 families, aged between 11 months and 56 years, from the USA, the United Kingdom, Estonia and Finland, from a family of Antillean and Moroccan ancestry, from an Ashkenazi Jewish family and from a consanguineous family from Pakistan [11]. The Levy series added 8 patients from 5 families, all monoallelic [3]. GeneReviews aggregated 28 individuals from 16 families (data from Beck 2020, Levy 2021, Seyama 2022 and Sager 2023), with denominators that vary by feature because not all reports describe all systems [1]. Later reports add at least five more individuals: an Italian woman [12], a Canadian boy [13], two Chinese monozygotic twins [14] and a Chinese infant [15]. No study describes the natural history prospectively; the data mix treated and untreated patients, and severity may be overestimated in probands and underestimated in carrier parents, whose assessment was often retrospective [1, 3].

Source: GeneReviews, Table 2 [1]; the same table was reproduced by Foti and colleagues in 2024 without adding cases [12].

The two original series differ in some frequencies. In the founding series, hypotonia and/or joint hypermobility occurred in 9/11 and growth differences in 8/11, whereas in the Levy series hypotonia and growth differences each occurred in 2/8, with intellectual disability in 6/8, autistic features in 5/8 and dysmorphism in 7/8 [3, 11]. The difference may reflect recruitment of the first series from patients with overgrowth and the variable expressivity of monoallelic alleles [3, 11].

3.2. Development and cognition

Developmental delay or intellectual disability is the most constant finding (25/26), with severity ranging from mild to severe, usually global (two or more domains among gross motor skills, fine motor skills and speech), although some patients have isolated delay in one domain [1]. In the founding series, intellectual disability, when formally assessed, was mild to moderate, and one individual had global delay without intellectual disability [11]. The extremes of the series illustrate the range: the least affected proband of the biallelic families had, at 7 years, an intelligence quotient (IQ) in the low average range, with dyslexia and dyscalculia, ADHD, obsessive-compulsive behaviours, anxiety and autistic features; the most affected, at 3 years, did not walk or talk, had seizures and was tube-fed; among the monoallelic patients, the most severely affected boy had, at 18 months, seizures since the first year, no head control, inability to sit or roll, faltering growth, hip dysplasia, nystagmus, strabismus and ptosis, and the least severely affected, at 10 years, had ASD, ADHD, anxiety and language delay, attended a special school, had a non-verbal IQ of 84 and was not dysmorphic [9, 11]. Most patients talk and walk, and independent walking appears in most between 15 and 36 months [1]. Hypotonia, present in 13/23, is most noticeable in infants and young children and may delay motor acquisition and expressive speech; spasticity has been described in one individual [1]. Movement disorders (7/23) include motor tics, myoclonus, dysmetria, abnormal posturing and dystonia [1]. The Canadian boy described by Man and colleagues, aged 5 years and 4 months, had global delay with marked delay in expressive language and social skills: at 3 years and 10 months he said only repeated syllables, pointed and understood simple commands, and tolerated only puréed food [13].

3.3. Epilepsy

Just over a third of patients have epilepsy (9/24), with varied seizure types [1]. The cases described in detail show the spectrum. Two siblings from one family had generalised tonic-clonic seizures, with occasional right central spike and slow-wave discharges on the electroencephalogram (EEG) [1, 3]. One individual in the founding series had infantile spasms with an abnormal EEG at 6 months [1, 11]. A Japanese girl had complex partial seizures with a left temporal and occipital focus [1, 22]. Absence seizures have been described in a girl, with a right-sided focus on EEG, and in a boy [1].

Epilepsy with sleep-activated discharges is a recurrent phenotype. The boy in the founding series started at 33 months with febrile partial seizures, followed by afebrile absences and limb myoclonus with preserved consciousness; the EEG evolved from bioccipital biphasic spikes to abundant bicentral spike-waves, more frequent in sleep, and then to continuous spike-waves during slow-wave sleep; seizures were refractory to sodium valproate, levetiracetam, lamotrigine and clobazam, and only the combination of sulthiame and corticosteroids was effective [1, 11]. The Turkish boy reported by Sager and colleagues, with developmental delay from 3 months, began at 5 years to have generalised tonic-clonic seizures and regression, with an EEG compatible with ESES [23]. The Italian patient reported by Foti and colleagues had her first generalised tonic-clonic seizure at 32 months and then focal seizures exclusively in sleep, with documented ESES and drug-resistant epilepsy until ethosuximide was introduced [12]. Sager and colleagues proposed reduced TET3 activity as a genetic cause of ESES [23]. The neurological regression observed in these patients is associated with poorly controlled epilepsy and not with intrinsic progression of the disease [1]. The episodes of reduced consciousness in the Canadian boy, one after mild head trauma and another after a meal, were not classified as epileptic seizures in the report [13].

3.4. Neuropsychiatric and behavioural manifestations

Autistic features or a formal diagnosis of ASD are present in about two thirds of the patients assessed (9/14), and a larger proportion (11/13) have difficulties or delay in social interaction compatible with social communication disorder [1]. Anxiety (8/11) and ADHD (6/13) are frequent [1]. Obsessive-compulsive behaviours and high pain tolerance were also described in the founding series [11]. Some patients develop depression or psychosis in adolescence or adulthood [1]. Levy and colleagues described a male proband with acute psychiatric symptoms and cognitive decline in adolescence (depression, severe anxiety with panic attacks, periods of psychosis with hallucinations, aggression and self-harm, alternating with normal periods), in whom mild delay in childhood was only recognised retrospectively; the mother carrying p.Val908Leu in the consanguineous family had a similar picture [3]. The 56-year-old man in the founding series, father of a proband, had mild to moderate intellectual disability, anxiety, depression and obesity [11].

3.5. Growth

Growth differences occur in 9/19: 6 with overgrowth (4 with macrocephaly, 1 with tall stature and 1 with macrocephaly and tall stature, the latter also with nephromegaly and cardiomegaly, suggestive of generalised somatic overgrowth) and 3 with undergrowth (3 with microcephaly, 2 of whom also had short stature); 10/19 had no differences [1]. All differences were postnatal, except in one individual with birth length above +2 standard deviations (SD); three individuals, two of them siblings, had birth weight below −2 SD [1]. In the founding series, true macrocephaly (head circumference ≥ +2 SD) occurred in 3 patients, and one child had advanced bone age [11]. The Italian patient had, at 39 months, a head circumference of 55 cm (+2 SD) and, in adulthood, height above the 97th centile and head circumference of 61 cm, with weight between the 3rd and 25th centiles [12]. Overgrowth and microcephaly with short stature are both compatible with the diagnosis, and neither excludes it [5].

3.6. Facial features

The common craniofacial features (21/23) are non-specific [1]. Most patients have a long face with a high and/or broad forehead; about half have a myopathic face with open mouth, prominent ears and a high-arched palate; about a third have a short nose with a long philtrum, and a slightly larger proportion have brachycephaly; some have thick or arched eyebrows, epicanthic folds or downslanting palpebral fissures; one individual had cleft lip and palate and an asymmetric mandible [1]. In the founding series, the short nose with long philtrum was more evident at younger ages [11]. In patients with overgrowth, the long face and high forehead are reminiscent of Sotos syndrome [11].

3.7. Eyes

Nine of 22 patients have ophthalmological findings [1]. The most common is strabismus (one patient with ophthalmoplegia), followed by myopia and hypermetropia; some have nystagmus or ptosis, one had nasolacrimal duct stenosis and another microphthalmia [1]. The Canadian boy had bilateral chorioretinal colobomas and a right iris coloboma, diagnosed at 4 months, with horizontal nystagmus and right anisometropic amblyopia, treated with atropine penalisation of the left eye because of intolerance of glasses and occlusion [13]. He is the first patient with colobomas described, and the authors base the biological plausibility on the role of tet3 in zebrafish retinal neurogenesis and in early eye development in Xenopus [13].

3.8. Hearing

Seven of 10 patients assessed had hearing loss: 4 with conductive loss (2 of whom had recurrent otitis media requiring tympanostomy tubes), 2 siblings with sensorineural loss and 1 with microtia and atresia of the left external auditory canal [1]. The Italian patient had mild bilateral conductive hearing loss on audiometry [12].

3.9. Musculoskeletal system

Nine of 19 patients have musculoskeletal findings: joint hypermobility (4), hip dysplasia in infancy (3), kyphosis and/or scoliosis (2) and inguinal hernia (1) [1]. Flat feet and scoliosis were also described in the founding series and scoliosis in the Italian patient [11, 12].

3.10. Neuroimaging

Brain magnetic resonance imaging (MRI) was performed in 13 patients and showed abnormalities in 8, many non-specific: enlarged extra-axial spaces in 4 unrelated patients (2 with mild ventriculomegaly, 1 with periventricular leukomalacia and 1 with agenesis of the corpus callosum and enlargement of the trigone and temporal horn, whose affected brother had isolated agenesis of the corpus callosum); white matter changes in a mother and her son; cerebellar hypoplasia with mega cisterna magna in 2; and hypoplasia of the midbrain tectum in 1 [1]. The Canadian boy had disorganised folia of the posterior vermis, the third patient described with cerebellar abnormalities [13]. The Italian patient had asymmetry of the occipital lobes and slight enlargement of the pericerebral CSF spaces, without malformation [12].

3.11. Gastrointestinal system

Eight of 18 patients had gastrointestinal manifestations: feeding difficulties in infancy (7), constipation (2) and pyloric stenosis (1) [1]. Some infants needed a nasogastric tube or gastrostomy; in the founding series, one patient had a gastrostomy and another gastro-oesophageal reflux with slow gastric emptying [1, 11].

3.12. Cardiovascular system

Five of 19 patients had congenital heart disease: valve disease in 3 (pulmonary stenosis; aortic regurgitation with ventricular septal defect; unspecified valve disease with an electrocardiographic abnormality), tetralogy of Fallot in 1 and a small, haemodynamically insignificant arterial collateral from the descending aorta in 1 [1]. Proband 1-II-1 also had cardiomegaly [11].

3.13. Genitourinary system

Cryptorchidism, hypospadias and nephromegaly, the latter in the context of generalised somatic overgrowth, have each been described in one patient [1].

3.14. Heterozygous carriers and adults

Parents carrying hypomorphic alleles in the biallelic families had mild phenotypes, mainly neuropsychiatric or learning-related, and all lived independently and/or worked [11]. In one family, the mother initially considered unaffected proved to have intellectual disability, anxiety and depression and had attended special education, which changed the classification of the variant from VUS to pathogenic [3]. The parents and maternal grandmother of the Canadian boy had suspected undiagnosed intellectual disability, and the carrier father had no apparent eye defects [13]. The oldest patient described was 56 years old, and the Italian patient completed her schooling with support, which shows that some adults have a phenotype compatible with independent living [11, 12]. The disorder is probably underdiagnosed in adults who have never had genomic testing [1].

4. Clinical Recognition and Red Flags

4.1. When to suspect

GeneReviews recommends considering the diagnosis in the presence of mild to severe developmental delay or intellectual disability associated with any of the following findings in childhood: generalised infant hypotonia; infant feeding difficulties; movement disorders (motor tics, myoclonus, dysmetria, posturing, dystonia); epilepsy (generalised tonic-clonic, focal and/or absence seizures); neuropsychiatric problems (anxiety, ADHD, ASD, impaired social interaction and, sometimes, depression or psychosis); growth differences, especially overgrowth (macrocephaly and/or tall stature), although microcephaly and short stature also occur; ophthalmological involvement (strabismus, refractive errors, nystagmus); musculoskeletal findings (joint hypermobility, hip dysplasia, scoliosis, kyphosis); and non-specific facial dysmorphism [1]. Because the presentation is usually global delay without distinctive findings, clinical suspicion alone is of limited value, and most diagnoses result from an exome or panel requested for intellectual disability, epilepsy or overgrowth [1, 12, 23].

4.2. Settings by age

In infants, the combination of hypotonia, feeding difficulties and motor delay is the usual presentation; macrocephaly or microcephaly, colobomas, congenital heart disease or infantile spasms may prompt the first assessment [1, 11, 13]. In preschool and school-age children, language delay, autistic features, ADHD, anxiety and epilepsy predominate; a Sotos-like facial appearance with overgrowth and a negative NSD1 test is a described setting [11, 12]. In adolescents and adults, the disorder may present as mild intellectual disability with psychiatric symptoms (anxiety, depression, psychosis) or be identified in a parent after a child's diagnosis [3, 11]. The Italian patient was diagnosed at 31 years of age, during a request for preconception counselling, after more than two decades of investigation [12], and a board member of the patient foundation reports her son's diagnosis at 20 years of age [19].

4.3. Warning and emergency signs

Neurological regression in a child with the diagnosis, especially with loss of language or cognitive skills, should prompt an EEG that includes sleep, because ESES has been described in at least three patients and responds variably to treatment [11, 12, 23]. Infantile spasms require urgent neurological assessment [11]. Onset of acute psychiatric symptoms in adolescence, with hallucinations, aggression or self-harm, has been described and warrants psychiatric assessment [3]. Food refusal, choking, faltering growth or recurrent respiratory infections suggest oromotor dysfunction with a risk of aspiration [1]. There is no newborn screening for this disorder, and the absence of a marker metabolite precludes biochemical screening [5].

5. Diagnosis: Criteria, Testing and Algorithms

5.1. Diagnostic criteria

There are no published consensus clinical criteria [1]. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic or likely pathogenic TET3 variant identified by molecular genetic testing; under the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) standards, the pathogenic and likely pathogenic classes are equivalent for clinical purposes [1, 30]. A heterozygous TET3 VUS neither establishes nor excludes the diagnosis, and the epigenetic signature can help classify uncertain variants [1]. In the rare cases with biallelic variants, the diagnosis rests on both variants, although methylation analysis may show that only one is pathogenic [1, 3].

5.2. Testing strategy

In a child with developmental delay or an adult with intellectual disability, GeneReviews allows starting with chromosomal microarray, followed by a multigene panel, exome or DNA methylation profiling [1]. Single-gene testing (TET3 sequencing followed by targeted deletion and duplication analysis) is rarely useful and is not recommended [1]. Intellectual disability or overgrowth panels vary in composition and sensitivity between laboratories, and some do not include TET3 [1, 5]. The exome gives results similar to those of a panel that includes the gene, with the advantage of covering recently described genes, and, given the rarity and recent delineation of the disorder, may be considered the test of choice; the genome is an alternative [1]. The National Center for Biotechnology Information (NCBI) Genetic Testing Registry (GTR) listed nine tests that include TET3 in October 2026 [31].

Source: GeneReviews [1], Levy 2021 [3], EpiSign v6.1 panel [16].

All 28 variants in GeneReviews were identified by sequencing (28/28), and the proportion detected by deletion and duplication analysis is unknown [1]. This 28/28 describes how the published cases were found, not the clinical sensitivity of sequencing, because patients with other mechanisms would not have been identified. Sequencing detects missense, nonsense and splicing variants and small intragenic deletions or insertions, but typically does not detect exon or whole-gene deletions or duplications, which require quantitative polymerase chain reaction (PCR), long-range PCR, multiplex ligation-dependent probe amplification (MLPA) or a targeted microarray [1].

5.3. DNA methylation episignature

Episignature analysis is a clinical test, not only a research test, and can be used as an initial test (followed by targeted TET3 sequencing to identify the variant) or to confirm the pathogenicity of a VUS [1, 32, 33]. The signature was built from bisulfite-converted whole-blood DNA hybridised to the Illumina Infinium MethylationEPIC array (865,918 probes, 777,162 after filtering) [3]. Probes were selected by a mean methylation difference of at least 10%, an adjusted p value below 0.001 and an area under the ROC (receiver operating characteristic) curve above 0.9, and a support vector machine classifier produces a methylation variant pathogenicity (MVP) score between 0 and 1 [3]. The final signature, obtained with 16 cases and 64 age- and sex-matched controls, has 567 probes, all hypermethylated [3]. In the initial signature, biallelic patients had scores above 0.95, monoallelic patients between 0.5 and 0.8 and controls close to zero, reflecting a dose effect [3]. In the multiclass model, tested against 46 neurodevelopmental disorders with 38 episignatures and more than a thousand samples, controls and the other syndromes had scores close to zero, except ADCADN, caused by activating DNMT1 variants, which had high, partially overlapping scores but was separable by hierarchical clustering and multidimensional scaling [3]. The controls were not matched for ethnicity and were mostly Western European [3].

The signature had a direct impact on variant classification. Two biallelic VUS combinations (p.Pro495Ser with p.Val1295Ile and p.Gly1505Arg with p.Trp1746Ser) had a control profile and were considered likely benign; the de novo variants p.Arg911Gln and p.Arg1683His were classified as likely pathogenic; and the c.2036dup variant, transmitted from mother to son, moved from VUS to pathogenic [3]. Screening of the EpiSign database, with more than a thousand undiagnosed patients, identified a 1-year-old boy with tetralogy of Fallot, short stature and dysmorphism, investigated for CHARGE and Kabuki syndromes, with a negative trio exome; exome reanalysis found c.738C>A p.(Cys246Ter), inherited from a mildly affected and possibly mosaic mother [3]. In the Canadian case, the paternal variant c.5020G>A p.(Ala1674Thr), classified as VUS, clustered concordantly with the monoallelic cases and had a high MVP score but below 0.5, without elevation for any other episignature; the moderate-confidence positive result allowed the functional criterion PS3 to be applied at full strength and the variant to be reclassified as likely pathogenic [13]. The authors discuss that moderate confidence may result from mosaicism, a hypomorphic allele, a partial functional impact or an overlapping condition, and that other laboratories might have downgraded the criterion to PS3 moderate and kept the VUS; the recommendations of the EpiSign laboratory network, based on 2399 cases, consider a high- or moderate-confidence positive result to be strong functional evidence, according to the same authors [13].

In 2021 the EpiSign Complete clinical test covered 44 conditions and did not include TET3 [3]. The EpiSign version 6.1 panel, published in September 2026 by the North West Genomic Laboratory Hub (Manchester) in partnership with the London Health Sciences Centre, includes Beck-Fahrner syndrome in its recessive and dominant forms and states that healthy carriers and individuals with incomplete penetrance are detectable [16]. The same panel includes episignatures for several differentials (Sotos, Tatton-Brown-Rahman, Luscan-Lumish, Rahman, Weaver and others of the Polycomb repressive complex 2 (PRC2), Kabuki, ADCADN and Beckwith-Wiedemann); for Malan syndrome, only the 19p13.13 deletion is detected, because NFIX sequence variants do not produce the same signature [16]. According to Man and colleagues, episignatures had been defined for 91 disorders at the time of publication [13].

5.4. Limits of testing

A negative exome does not exclude the diagnosis: one of Levy's patients was only identified by the episignature, after a negative trio exome in which the variant was present but had not been prioritised before the disorder was described, which justifies periodic reanalysis of negative exomes [3]. The exome does not assess non-coding variants or reliably detect low-level mosaicism [1, 11]. Leucocyte DNA may not detect parental somatic mosaicism and does not detect exclusively germline mosaicism [1]. The episignature measures blood and not brain, does not identify the variant and may give moderate confidence for hypomorphic or mosaic alleles [3, 13]. The high proportion of VUS in ClinVar (400 of 624 records) shows the weight of missense variant interpretation in this gene [29].

5.5. Report content, VUS and segregation

The report should identify the gene, the versioned transcript (NM_001287491.2), the variant in HGVS nomenclature (c. and p.), the zygosity, the origin when the trio has been analysed and the ACMG/AMP class [6, 30]. When the laboratory uses another transcript, such as NM_001366022.1, conversion to MANE avoids duplicate records of the same variant [6]. Faced with a VUS, the tools available are family segregation with careful phenotypic assessment of the parents, episignature analysis and, in research, functional 5hmC production assays [3, 11]. Segregation requires caution: a healthy sister with the same two variants as the proband allowed those variants to be considered benign, but a mother initially classified as unaffected proved to be affected after targeted assessment [3]. In 2024 the Italian patient still had a de novo variant classified as VUS by the laboratory, and the authors argued for causality on the basis of the phenotype [12].

5.6. Prenatal and preimplantation diagnosis

Once the familial variant or variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. No characteristic ultrasound findings have been described; the few published prenatal data are birth weight below −2 SD in three patients and length above +2 SD in one [1].

6. Differential Diagnosis

6.1. Principles

The typical presentation is global developmental delay without distinctive findings, so the differential covers all causes of non-syndromic and syndromic intellectual disability with dominant, recessive and X-linked inheritance [1]. Within that universe, the other MDEM and the overgrowth–intellectual disability syndromes come closest, through the combination of intellectual disability, autistic features, growth differences and a long face with a high forehead [1, 11]. Clinical discrimination is limited, and the discriminating test is almost always genomic: the exome or genome resolves most monogenic differentials, and episignature analysis allows several MDEM with a validated signature to be distinguished in a single test [1, 3, 16].

Sources: GeneReviews, Table 3 [1]; Oxford Desk Reference [35]; Beck 2020 [11]; Levy 2021 [3]; Foti 2024 [12]; Man 2024 [13]; Privitera 2026 [26]; Fleming 2024 [27]; EpiSign v6.1 panel [16].

6.2. Overgrowth–intellectual disability syndromes

The initial proband in the founding series was investigated for Sotos, Malan and Beckwith-Wiedemann before the exome, and the Italian patient had a negative NSD1 study before diagnosis [11, 12]. In patients with macrocephaly and intellectual disability, the Beck-Fahrner facial appearance (long face, high forehead) is reminiscent of Sotos, but it lacks the combination of sparse frontotemporal hair, malar flushing and long chin, the overgrowth is postnatal and a third of patients have undergrowth [1, 11, 35]. The general approach to overgrowth, defined as height or head circumference above +2 SD (about the 98th centile), includes a three-generation pedigree with birth weights and parental growth, pregnancy history (gestational diabetes, assisted reproduction, polyhydramnios), the neonatal period (hypoglycaemia, abdominal wall defects), the growth chart, examination of the spine and cardiac auscultation, and investigation by array, panel, exome or genome, with FMR1 testing when there is developmental delay [35]. Tatton-Brown-Rahman and Heyn-Sproul-Jackson syndromes, both caused by the DNMT3A gene, illustrate the effect of mechanism: loss of function causes overgrowth, and gain of function causes microcephaly and short stature [1].

6.3. Differential of epilepsy with sleep activation

In a child with regression and ESES, reduced TET3 activity enters the genetic differential, alongside structural causes and other monogenic causes of epileptic encephalopathy with spike activation in sleep [23]. In the three patients with this phenotype, epilepsy or macrocephaly panels were negative or did not include TET3, and the diagnosis came from an exome [11, 12, 23].

6.4. Coloboma, heart disease and other settings

The case with colobomas and the case with tetralogy of Fallot were initially assessed as possible CHARGE or Kabuki syndromes, two MDEM associated with coloboma or congenital heart disease [3, 13]. In the Italian patient, two compound heterozygous LRP2 VUS suggested Donnai-Barrow syndrome, but the prominent eyes, downslanting fissures, high myopia, coloboma and severe intellectual disability were absent, and her healthy siblings carried one of the variants [12]. The same patient had testing for Prader-Willi and Angelman syndromes (15q11-q13 methylation), fragile X (FRAXA and FRAXE), storage disorders (skin biopsy, without granular osmiophilic deposits) and a metabolic work-up (very long-chain fatty acids, organic acids), all normal [12].

6.5. Laboratory differential of the episignature

The most relevant laboratory overlap is with ADCADN, caused by activating DNMT1 variants: samples from this disorder have high scores on the TET3 classifier and hypermethylation in 34 of the 50 differentially methylated regions, but separate on hierarchical clustering [3]. The authors interpret the similarity as reflecting the balance between a hyperactive writer (DNMT1) and a deficient eraser (TET3), both with a net gain of methylation [3]. Correlation with the clinical phenotype and sequencing of TET3 and DNMT1 resolve the ambiguity [3, 13].

7. Treatment and Risk Management Strategies

7.1. Principles and status of recommendations

There is no mechanism-directed treatment, no clinical practice guideline and no specific consensus for Beck-Fahrner syndrome [1, 5]. The GeneReviews recommendations apply standard measures to each manifestation, rest on 28 individuals from 16 families and are not derived from trials; no antiseizure medication has shown preferential efficacy in this disorder [1, 5]. The aim is to improve quality of life, maximise function and reduce complications through multidisciplinary supportive care [1]. A search for guidelines in PubMed, ClinicalTrials.gov, ERN ITHACA, NORD and the patient foundation found no specific documents, which does not prove that none exist [17–19, 36].

Source: GeneReviews, Table 5 [1].

7.2. Epilepsy and electrical status epilepticus during sleep

Seizure treatment follows the general principles of epilepsy care, chosen according to seizure type and electroclinical syndrome [1]. The available data on response come from three individual reports with ESES, and none allows drugs to be compared. The boy in the founding series was refractory to sodium valproate, levetiracetam, lamotrigine and clobazam and responded only to the combination of sulthiame with corticosteroids [1, 11]. The Turkish boy received, during the first 6 months, valproic acid with immunotherapy (pulsed corticosteroids and intravenous immunoglobulin, according to GeneReviews), with clinical improvement independent of the EEG; over the following 6 months, clobazam added to valproate improved the EEG, with no regression after immunotherapy was stopped [1, 23]. The Italian patient received phenobarbital at maximum dose, carbamazepine, clobazam, vigabatrin, valproate and lamotrigine (stopped quickly because of marked sedation, asthenia and loss of coordination), with control only after 8 years of age and complete control with ethosuximide, which allowed the other drugs to be withdrawn; she had been free of sleep seizures since 14 years of age, with a normal EEG at 16 years, and off medication in adulthood [12]. The reports do not publish doses.

The following doses come from the official labels of the US Food and Drug Administration (FDA) and from the summaries of product characteristics (SmPC) approved by INFARMED, because there is no published dose for this syndrome and no specific guideline in the sources consulted. Use in Beck-Fahrner syndrome is an extrapolation from the approved indications, and ESES is not an approved indication for any of these drugs.

Sulthiame, effective in combination with corticosteroids in the boy in the founding series, has no authorised medicinal product in Portugal according to Infomed [42], and the sources consulted did not include a label with dosage; the pulsed corticosteroids and intravenous immunoglobulin used in the Turkish boy also have no regimen published in the reports, so no doses are given [11, 23]. Ethosuximide also has no authorised medicinal product in Portugal according to Infomed [42]. Levetiracetam, lamotrigine, phenobarbital, carbamazepine and vigabatrin were used without efficacy in the reports, without this allowing general conclusions [11, 12].

Valproate has two particularities in this population. The Portuguese SmPC and the FDA label identify young children with severe epilepsy associated with mental retardation or brain injury, on polytherapy, as the group at highest risk of fatal hepatotoxicity, a profile that includes some patients with Beck-Fahrner syndrome [40, 41]. Valproate is contraindicated in POLG-related disease, urea cycle disorders, uncorrected primary carnitine deficiency, hepatitis and porphyria [41]. The labels differ in the therapeutic range (50–100 µg/mL in the FDA label, 40–100 mg/L in the SmPC, equivalent units) and in the dose threshold requiring caution (60 mg/kg/day in the FDA label, 50 mg/kg/day in the SmPC) [40, 41].

7.3. Development, motor skills, feeding and communication

The model described in GeneReviews corresponds to the US organisation of services and varies between countries [1]. From 0 to 3 years, early intervention is recommended with occupational therapy, physiotherapy, speech and feeding therapy, infant mental health and specialised educators; from 3 to 5 years, preschool education with an individualised education plan; at all ages, follow-up in developmental paediatrics, a plan reviewed annually in the least restrictive possible environment, vision and hearing consultants on the educational team and transition planning in adolescence [1]. Physiotherapy seeks to maximise mobility and reduce late orthopaedic complications, such as scoliosis and hip dislocation, with orthoses and adapted equipment when needed; occupational therapy works on the fine motor skills needed for feeding, hygiene, dressing and writing [1]. Oromotor function should be assessed at every visit; choking, faltering growth, frequent respiratory infections or food refusal warrant clinical swallowing assessment and/or a radiological study, with feeding therapy, changes in food texture or temperature and, in severe cases, a nasogastric tube or gastrostomy [1]. Assessment for augmentative and alternative communication with a speech and language therapist is recommended, because these devices do not hinder the development of verbal speech [1]. The Italian patient completed her schooling with educational support and speech therapy [12].

7.4. Behaviour and mental health

Interventions for ASD include applied behaviour analysis, individual and delivered by a certified behaviour analyst; developmental paediatrics guides behavioural strategies and medication, for example for ADHD, and severe aggression or destructive behaviour warrant referral to child psychiatry [1]. Standard ADHD and anxiety medication may be effective, but none has been studied in this disorder, and the sources do not describe specific drugs or responses [1]. The description of psychosis, depression and severe anxiety with onset in adolescence or adulthood, in patients and in carrier parents, supports lifelong mental health surveillance [3, 11].

7.5. Regulatory status

No medicinal product has an approved indication for Beck-Fahrner syndrome, and there is no orphan designation, regulatory application or registered trial [17]. The table compares the status of the antiseizure medications used in the reports.

Sources: FDA labels [37, 38, 40]; INFARMED SmPCs [39, 41]; Infomed search [42]. The sources consulted did not include the European centralised SmPCs or the Brazilian registration of these drugs.

7.6. Pregnancy, contraception and paternal exposure

Women with epilepsy have higher mortality in pregnancy, and antiseizure medications reduce that risk; fetal exposure to antiseizure medications may increase the risk to the fetus, depending on the drug, the dose and the stage of pregnancy, but that risk is often lower than that of untreated maternal seizures, so treatment is continued and discussion of risks and benefits should precede conception, with a possible switch to a lower-risk drug [1, 43]. Valproate has a high teratogenic potential, with a risk of congenital malformations and neurodevelopmental disorders after exposure in utero; in Portugal it is contraindicated in pregnancy, unless there is no suitable alternative, and in women of childbearing potential outside the conditions of the pregnancy prevention programme, and in girls and women of childbearing potential it should only be used if other treatments are ineffective or not tolerated, initiated by a specialist [41]. The FDA label likewise advises against valproate in women who are pregnant or planning pregnancy and in women of childbearing potential unless alternatives have failed [40]. In men treated with valproate, the Portuguese SmPC recommends informing them of a possible risk of neurodevelopmental disorders in children conceived during treatment or in the following 3 months [41]. Clobazam used in pregnancy may cause neonatal sedation and withdrawal syndrome [38]. The ethosuximide label recommends enrolling exposed pregnant women in the North American antiepileptic drug pregnancy registry [37]. Because intellectual disability affects some women with the syndrome, information on these risks should be adapted to decision-making capacity and involve caregivers when appropriate [1].

7.7. Available therapeutic evidence

There are no clinical trials; the evidence is limited to case reports.

Sources: [1, 11, 12, 23].

These reports do not allow efficacy to be inferred: each describes one patient, without a comparator, with sequential or combined treatments and without separating the effect of treatment from the spontaneous course of the epilepsy. The report of the Italian patient is internally inconsistent about the date medication was stopped (around 10 years at one point in the text, 24 years at another) [12]. No negative, suspended or withdrawn trials are registered [17].

7.8. Developments in the last 12 months and research

Between November 2025 and October 2026, the literature on the syndrome was limited to case reports and a chromosomal deletion study, all at the level of descriptive evidence [15, 26]. A Chinese report from 2025 described a 9-month-old infant with hypotonia, global psychomotor delay, a long face and open mouth, with a de novo frameshift variant in exon 7 classified as pathogenic [15]. An Italian study from 2026 delineated the 2p13.2-p11.2 deletion syndrome by optical genome mapping and proposed TET3 as a gene that aggravates the phenotype [26]. In September 2026, version 6.1 of the EpiSign clinical panel began listing Beck-Fahrner syndrome in its dominant and recessive forms [16]. In October 2026 ClinicalTrials.gov had no study registered for TET3, Beck-Fahrner or BEFAHRS, nor any natural history registries [17]. ERN ITHACA opened a call for collaboration, now closed, coordinated by the Institut Imagine (Paris), to delineate the clinical and molecular spectrum with growth, neurodevelopmental and episignature data; the results had not been published at the time of the search [18]. No applicable regulatory announcements, opinions or authorisations were identified.

Preclinical research by Fahrner's group includes refinement of the methylation profile, human cell models and collection of neuropsychological data as potential outcome measures for future trials [1]. Fahrner and Bjornsson discuss postnatal plasticity in the MDEM and the therapeutic prospects for the group, although no intervention for TET3 deficiency is in clinical development [1, 25]. The patient foundation states its mission as accelerating research towards a cure [19].

7.9. Agents to avoid, perioperative care and transition

There are no drugs specifically contraindicated because of the syndrome [1]. In the labels of the antiseizure medications used, the points relevant to this population are caution with valproate in young children with severe epilepsy and developmental delay, the possibility that ethosuximide alone increases tonic-clonic seizures in epilepsies with several seizure types, and the combination of clobazam with opioids, which may cause profound sedation, respiratory depression and death [37, 38, 41]. Lamotrigine caused marked sedation, asthenia and incoordination in the Italian patient, an individual observation that does not define a contraindication [12]. The sources consulted do not describe anaesthetic complications or perioperative recommendations specific to the syndrome; congenital heart disease, oromotor dysfunction and benzodiazepine use are the factors to consider in planning [1, 38]. Transition to adult care should be planned in adolescence, integrated into the educational plan, and include mental health surveillance, review of the need for antiseizure medication and reproductive counselling [1, 3, 12].

8. Reproductive Options and Family Counselling

8.1. Mode of inheritance and origin of variants

For counselling, GeneReviews treats the syndrome as autosomal dominant: individuals with a pathogenic variant are affected, albeit with variable expressivity [1]. Of the 12 probands with a heterozygous variant brought together in GeneReviews, 9 had a de novo variant and 3 inherited it from an affected parent [1]. Six individuals from three families had biallelic variants inherited from heterozygous parents, who often had mild features [1, 11, 22]. In the Japanese family with two biallelic children, neither parent was described as affected, although it is unclear whether they were fully assessed [1, 22]. The choice between the dominant and the recessive model in a given family depends on careful phenotypic assessment of the parents and, when available, on methylation analysis, which detects carriers with a mild phenotype or incomplete penetrance [3, 16].

8.2. Assessment of the parents of a proband

In an isolated case, testing the parents for the variant or variants found is recommended [1]. If the heterozygous variant is not found in either parent, with biological parentage confirmed, the variant is de novo in the proband or there is germline (or somatic and germline) mosaicism in a parent; leucocyte DNA may not detect somatic mosaicism and does not detect exclusively germline mosaicism [1]. In a biallelic proband in whom only one parent has one of the variants, the other may have arisen de novo in the proband or as a post-zygotic event in a mosaic parent [1, 44]. Phenotypic assessment of the parents should include their educational, cognitive and psychiatric history, because a mother initially classified as unaffected had intellectual disability, anxiety, depression and special education [3]. A mildly affected, possibly mosaic mother who transmitted the variant to her son has been described [3].

8.3. Recurrence risks

The offspring of a heterozygous individual have a 50% probability of inheriting the variant, unless the partner also has a TET3 variant; consanguinity increases that probability [1]. Severely affected individuals with biallelic variants have no known offspring [1]. The Italian patient sought preconception counselling in adulthood, and it was this request that led to the exome that established the diagnosis; for a heterozygous de novo variant, the risk to offspring follows the 50% figure of the dominant model [1, 12]. The risk to other relatives depends on the status of the parents [1].

8.4. Cascade testing and carriers

Testing of at-risk relatives follows identification of the variant in the proband; GeneReviews does not define specific surveillance for relatives and refers to genetic counselling [1]. Heterozygous relatives in biallelic families should be informed that they may have mild manifestations, mainly learning-related and psychiatric [3, 11]. Segregation can also exclude pathogenicity, as in the family in which a healthy sister had the same two variants as the proband [3].

8.5. Prenatal and preimplantation diagnosis

Once the familial variant or variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible; views on their use vary among professionals and families and the decision is personal [1]. Risk determination and discussion of these options should ideally take place before pregnancy [1]. In families in which the variant was inherited from a parent with a mild phenotype, counselling should explain that severity in the child cannot be predicted from the parent [1, 3].

8.6. Minors and young adults

Genetic counselling should be offered to affected or carrier young adults, including information on reproductive risk [1]. The sources consulted do not specifically address testing of asymptomatic minors in this syndrome; GeneReviews does not define surveillance or preventive measures for heterozygous relatives, which should be explained when testing of a minor sibling is discussed [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Prevalence is unknown [1]. Orphanet assigns the point prevalence class <1/1,000,000, a worldwide estimate based on the founding paper, and records 5 cases or families, a count that has not been updated [2]. GeneReviews brought together 28 individuals from 16 families up to 2023, and the author was aware of unpublished cases [1]. Seyama and colleagues counted 14 published individuals in 2021, including their three patients [22]. With the later reports reviewed, at least 33 affected individuals have described TET3 sequence variants [12–15]. The patient foundation's gallery shows 21 individuals, mostly from the USA [19]. These figures measure published cases or organised families and not frequency in the population; there are no population studies, newborn screening data or estimates of diagnostic yield in intellectual disability cohorts [5]. In a Chinese series of 32 twin pairs with neurodevelopmental disorders, the overall molecular diagnostic yield was 17.2% (11/64), and one monozygotic pair had the TET3 variant [14]. GeneReviews acknowledges underdiagnosis in adults without genomic testing [1].

9.2. Geographical distribution and ancestry

The published patients come from the USA, the United Kingdom, Estonia and Finland, from families of Antillean, Moroccan and Ashkenazi Jewish ancestry, from a consanguineous Pakistani family, and from Japan, Turkey, Italy, Canada and China [11–15, 20, 22, 23]. The foundation's gallery also includes individuals from Pakistan, Australia, the Netherlands, Canada and England [19]. There is no founder variant, and the only homozygosity occurred in a context of consanguinity [11]. The p.Arg752Cys variant, later considered likely benign, had 29 alleles in gnomAD with no homozygotes, whereas the pathogenic variants of the founding series were absent from that database [11]. The controls used to build the episignature were mostly of Western European ancestry, without matching for ethnicity, which limits direct transfer to other populations [3]. The sources consulted contain no data from Portugal or Brazil, which does not demonstrate the absence of cases in those countries.

9.3. Special populations

In women of childbearing potential with epilepsy, the choice of antiseizure medication should take into account the valproate pregnancy prevention programme (7.6) [41]. In adults, the phenotype may be predominantly psychiatric or one of mild intellectual disability, and carrier parents may have been diagnosed only after their child [3, 11]. In consanguineous families, the possibility of biallelic variants should be considered [1, 20].

9.4. Reference networks and patient organisations

The relevant European network is ERN ITHACA (rare congenital malformations and intellectual disability), whose call for collaboration on the syndrome was coordinated by Maud de Dieuleveult and Valérie Cormier-Daire at the Institut Imagine (INSERM U1163, Paris) [18]. The Beck-Fahrner Syndrome Foundation, a non-profit organisation founded in 2021 in the USA by the mother of a diagnosed child, runs a support group, virtual parent meetings, educational sessions, information material, support packages and a travel grant for families, and has Jill A. Fahrner on its scientific board [19]. Johns Hopkins University runs a multidisciplinary epigenetics and chromatin clinic that follows patients with MDEM and imprinting disorders [1]. The National Organization for Rare Disorders (NORD) publishes a summary for families, updated in July 2024 [36]. GeneReviews also lists the Parent to Parent group, the MotherToBaby service for medication in pregnancy and the resources of the Epilepsy Foundation [1]. The sources consulted do not identify associations in Portugal or Brazil.

10. Illustrative Clinical Case

10.1. Epilepsy with ESES, macrocephaly and diagnosis at 31 years of age

In 2024 Foti and colleagues described an Italian woman, the third child of healthy, non-consanguineous parents, born at 39 weeks by caesarean section, with a weight of 3.4 kg (50th centile) and head circumference of 36.5 cm (75th–90th centiles) [12]. She had motor delay, with first steps at 20 months and unsteady gait until 3 years, and slow language acquisition [12]. At 32 months she had her first generalised tonic-clonic seizure, treated with rectal diazepam and hospital admission; the EEG showed left parieto-temporal slow spike-wave complexes, and the metabolic work-up (very long-chain fatty acids, urinary organic acids, apolipoproteins) was normal [12]. MRI at 3 years showed no malformations, only asymmetry of the occipital lobes with right predominance and slight enlargement of the pericerebral CSF spaces, findings confirmed on 1.5 T MRI at 18 years (figure 1 of the paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC11395583/figure/ijms-25-09676-f001/) [12]. Phenobarbital initially controlled the seizures but caused ataxia and dysarthria; at 39 months she had macrocephaly (head circumference 55 cm, +2 SD) with a length of 95 cm (50th centile) [12].

The epilepsy evolved into focal seizures only during sleep, with lateral deviation of the mouth, and the EEG documented ESES (figure 2 of the paper, EEG at 14 years: https://pmc.ncbi.nlm.nih.gov/articles/PMC11395583/figure/ijms-25-09676-f002/) [12]. Phenobarbital at maximum dose and polytherapy with carbamazepine, clobazam, vigabatrin, valproate and lamotrigine did not control the seizures, and lamotrigine was stopped because of sedation, asthenia and incoordination; a satisfactory combination was obtained only after 8 years of age, and complete control came with ethosuximide, which allowed the other drugs to be withdrawn [12]. She had no sleep seizures after 14 years of age, the EEG was normal at 16 years and medication was stopped in adulthood; a recent EEG showed only frontal slow waves during hyperventilation, without clinical correlate and without indication for treatment [12]. At 10 years she had mild cognitive impairment, poor abstraction, ADHD and repetition of learned patterns; with educational support and speech therapy she completed her schooling [12].

The diagnostic journey lasted more than two decades. Karyotype, FRAXA and FRAXE testing, skin biopsy and 15q11-q13 methylation were normal; at 22 years, at her first genetics clinic appointment, she had tall stature, macrocephaly and normal weight; array-CGH showed a 272 kb 11p12 microdeletion inherited from her mother, considered non-causal; NSD1 and a 109-gene epilepsy panel were negative; a trio macrocephaly and developmental delay panel, in 2019, found two compound heterozygous LRP2 VUS, without a Donnai-Barrow phenotype and with healthy siblings carrying one of the variants; audiometry showed mild bilateral conductive hearing loss [12]. In 2023, following a request for preconception counselling, clinical trio exome sequencing identified the de novo variant NM_001287491.2:c.2867G>A p.(Arg956Gln), absent from the parents, the siblings and population databases, at a conserved residue and with mostly deleterious predictors; the laboratory classified it as VUS, and the authors argued for causality on the basis of the phenotype [6, 12]. The final phenotype included mild intellectual disability, height above the 97th centile, head circumference of 61 cm, weight between the 3rd and 25th centiles, ataxia, scoliosis, ESES, refractory epilepsy in childhood, a high and broad forehead, long face, epicanthic folds, arched eyebrows, simplified ears, long neck, broad and long nose with smooth philtrum and orofacial dyspraxia (figure 4 of the paper, face at 32 years: https://pmc.ncbi.nlm.nih.gov/articles/PMC11395583/figure/ijms-25-09676-f004/; scheme of TET3 variants in figure 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC11395583/figure/ijms-25-09676-f003/) [12].

The case illustrates three points of general value: epilepsy with sleep activation may be the dominant clinical problem; the overgrowth phenotype with macrocephaly is reminiscent of Sotos and leads to negative targeted tests; and a de novo missense variant may remain a VUS without functional evidence, a situation in which episignature analysis, not performed in this case, would have been the appropriate tool [1, 12, 13]. The sequence of drugs used was individual and does not constitute a recommended regimen; ethosuximide has no approved indication for ESES (7.2) [37].

10.2. Coloboma and reclassification of a VUS by the episignature

Man and colleagues described a Canadian boy aged 5 years and 4 months, the son of a 25-year-old primigravida mother of Dutch, Italian and African ancestry and a Caucasian father, born at term without complications (weight 2856 g, head circumference 33.5 cm) [13]. At 7 weeks an abnormal right pupil was noticed, and at 4 months bilateral chorioretinal colobomas, a right iris coloboma and horizontal nystagmus were diagnosed [13]. He had global delay with marked delay in expressive language and social skills, ASD diagnosed at 4 years and feeding limited to purée; MRI showed the colobomas, more marked on the right, and disorganised folia of the posterior vermis; the facial features included a broad forehead, high anterior hairline, downslanting fissures, triangular face, prominent nasal bridge, slightly broad nasal tip and a low-set left ear (figure 1 of the paper, legend consulted; https://doi.org/10.1002/ajmg.a.63864) [13]. The microarray revealed a 1q25.2 microduplication of uncertain significance, considered non-contributory, and trio exome sequencing identified the paternal variant c.5020G>A p.(Ala1674Thr) in NM_001287491.2, classified as VUS [13]. EpiSign analysis showed clustering with the monoallelic cases and a high MVP score but below 0.5, without elevation for other syndromes, and the laboratory applied the PS3 criterion at full strength and reclassified the variant as likely pathogenic (figure 2 of the paper, legend consulted) [13]. The carrier father had suspected intellectual disability, as did the mother and maternal grandmother, and was not formally assessed because he was not involved in the child's care [13]. The case broadens the ocular phenotype and shows the usefulness and the limits of the episignature with hypomorphic alleles [13].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

It is not known whether life expectancy is reduced; the oldest patient described was 56 years old [1, 11]. The disorder is not considered progressive, but poorly controlled epilepsy, especially ESES, may cause neurological regression [1, 23]. Most patients talk and walk, with independent walking between 15 and 36 months [1]. Intellectual disability ranges from mild to severe, and some adults live independently or work, especially among carriers of hypomorphic alleles [1, 11]. Epilepsy (9/24) remitted in at least one case: the Italian patient became seizure-free and off medication in adulthood, with schooling completed and a good quality of life, an isolated observation that illustrates the variability [12]. Psychiatric symptoms may appear or worsen in adolescence and adulthood [1, 3]. No tumour risk has been described, and there is no recommendation for cancer surveillance [1].

11.2. Initial assessment after diagnosis

After diagnosis, GeneReviews recommends measuring growth parameters, including head circumference; neurological assessment of tone and movement disorders, with brain MRI if clinically indicated and EEG if seizures are suspected; assessment by physical and rehabilitation medicine, physiotherapy and occupational therapy; developmental assessment (motor, adaptive, cognitive and language); screening, from 12 months, for sleep disorders, ADHD, anxiety, social communication disorder and ASD; musculoskeletal examination (joint hypermobility, scoliosis, flat feet, hip dysplasia); feeding and nutritional assessment; ophthalmological examination; audiological assessment with investigation for chronic otitis media and ear anomalies; echocardiogram and, where appropriate, electrocardiogram; genital examination in boys and, where appropriate, abdominal or renal ultrasound; genetic counselling; and connection with family support resources and social services [1].

11.3. Surveillance

The first eight rows reproduce in substance the GeneReviews surveillance (at each visit for growth, neurology, development, behaviour, constipation, the musculoskeletal system and family needs; at least annually for eyes and hearing) [1]. GeneReviews does not set the frequency of visits, which depends on age and needs; annual ophthalmological and audiological surveillance is the part most easily forgotten [1, 5].

12. Summary and Concluding Remarks

Beck-Fahrner syndrome results from reduced activity of TET3, the dioxygenase that initiates active DNA demethylation, and was the first Mendelian disorder described in the machinery that removes methylation [11]. Clinically it manifests as developmental delay or intellectual disability (25/26), autistic features and social communication disorder, anxiety, ADHD, hypotonia, epilepsy in about a third (9/24, including ESES), growth differences in both directions (9/19), hearing loss that is mostly conductive (7/10), ophthalmological and musculoskeletal findings and, less often, congenital heart disease, with a non-specific long face and high forehead [1]. Inheritance is described as autosomal dominant with variable expressivity, with most monoallelic variants de novo, and the families with biallelic hypomorphic variants, recorded as recessive by Orphanet, are interpreted by GeneReviews as the severe end of a dose effect in which carrier parents have a mild phenotype [1–3]. Diagnosis is made by exome or genome sequencing, preferably as a trio, and the whole-blood hypermethylation episignature, now available on a clinical panel, confirms the diagnosis, distinguishes monoallelic from biallelic patients and reclassifies VUS [1, 3, 13, 16]. The reference transcript is NM_001287491.2, and variants published on another transcript should be converted [6]. There is no specific treatment and there are no trials; management is multidisciplinary and symptomatic, with conventional antiseizure treatment, the evidence on ESES being limited to individual reports and the doses taken from the labels [1, 17]. Surveillance includes growth, neurology, development, behaviour, feeding and the spine at each visit, and eyes and hearing at least annually, with attention to mental health in adolescence and adulthood [1, 3]. Prevalence is unknown, with at least 33 published individuals, and delineation of the spectrum depends on larger series such as the one promoted by ERN ITHACA [1, 18].

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