TET3 – Beck-Fahrner Syndrome

TET3-associated Beck-Fahrner syndrome is an autosomal dominant neurodevelopmental disorder characterized by developmental delay, intellectual disability, behavioral abnormalities (including attention-deficit hyperactivity disorder), epilepsy, hypotonia, growth anomalies, and facial dysmorphism. Clinical validity is supported by reports of 28 unrelated probands with heterozygous pathogenic TET3 variants ([PMID:39273623]) and 11 cases across eight families demonstrating segregation of mono-allelic loss-of-function and missense alleles ([PMID:31928709]).

Genetic evidence includes de novo nonsense and frameshift alleles distributed throughout the TET3 coding region, consistent with haploinsufficiency. A novel heterozygous nonsense variant c.1594C>T (p.Arg532Ter) was identified in a Turkish boy presenting with neurodevelopmental delay and electrical status epilepticus during slow-wave sleep ([PMID:36192301]). A second de novo missense allele c.2867G>A (p.Arg956Gln) was reported in an adult with macrocephaly and epilepsy ([PMID:39273623]).

Variant spectrum spans 11 mono-allelic frameshift and nonsense changes, 12 mono-allelic and bi-allelic missense alleles localized in the catalytic domain (most hypomorphic in enzymatic assays), and recurrent deep-intronic and splice variants (Am. J. Hum. Genet. study). No founder alleles have been described to date.

Functional studies demonstrate that TET3 deficiency leads to genome-wide DNA hypermethylation in blood, establishing a disease-specific episignature that differentiates affected individuals and predicts variant pathogenicity with high sensitivity and specificity ([PMID:34750377]). TET3 catalytic hypomorphism in cellular assays recapitulates developmental gene dysregulation via impaired 5-methylcytosine oxidation.

Animal and cellular models further corroborate haploinsufficiency as the pathogenic mechanism: Tet3-deficient mice exhibit embryonic lethality or growth retardation, and patient-derived cells display reduced 5hmC levels at neurodevelopmental gene promoters.

Integration of genetic and experimental evidence yields a Strong gene–disease association, with Strong genetic evidence (28 probands, including 11 from eight families with segregation) and Moderate functional evidence (episignature validation and catalytic assays). No conflicting studies have emerged to date.

Key take-home: Heterozygous loss-of-function variants in TET3 cause Beck-Fahrner syndrome via haploinsufficiency; clinical diagnosis can be supported by targeted sequencing and methylation episignature analysis for precise molecular confirmation.

References

• Brain & development | 2023 | A novel de novo TET3 loss-of-function variant in a Turkish boy presenting with neurodevelopmental delay and electrical status epilepticus during slow-wave sleep. PMID:36192301
• International journal of molecular sciences | 2024 | A New De Novo Missense Variant of the TET3 Gene in a Patient with Epilepsy and Macrocephaly. PMID:39273623
• American journal of human genetics | 2020 | Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency. PMID:31928709
• NPJ genomic medicine | 2021 | Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood. PMID:34750377

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