DNMT3A – Tatton-Brown-Rahman overgrowth syndrome

Tatton-Brown-Rahman syndrome (TBRS; MONDO:0014382) is a congenital autosomal dominant overgrowth disorder caused by heterozygous germline variants in the DNA methyltransferase gene DNMT3A. Individuals present with postnatal tall stature, macrocephaly, intellectual disability, and characteristic facial features. To date, over 100 unrelated probands with de novo DNMT3A variants have been reported ([PMID:38937076]), and the spectrum now includes inherited cases, highlighting a definitive gene–disease relationship.

DNMT3A variants in TBRS comprise missense changes clustering in the PWWP and methyltransferase domains and loss‐of‐function alleles. More than 60 unique variants have been described, including recurrent hotspot mutations at codon Arg882. For example, the c.2644C>T (p.Arg882Cys) variant is frequently observed in both TBRS and somatic hematologic malignancies ([PMID:28941052]). Two families with vertical transmission—an Old Order Amish sibship and a French‐Canadian kindred—confirmed autosomal dominant inheritance and segregation in six affected relatives ([PMID:27701732]).

Inheritance is nearly always autosomal dominant, with most variants occurring de novo; however, familial transmission has been documented in sibships where four and two individuals, respectively, inherited pathogenic alleles ([PMID:27701732]). These segregation data, together with multiple independent de novo occurrences, strengthen the genetic association.

Clinical studies demonstrate universal intellectual disability (100% of 24 French patients; [PMID:38937076]) and overgrowth (>80% of 55 individuals; [PMID:29900417]), with macrocephaly (74%), hypotonia (54%), joint hypermobility (74%), obesity (67%), and neuropsychiatric comorbidities in a significant subset. Facial dysmorphisms include low‐set eyebrows and prominent incisors. A minority of patients develop vascular complications, pituitary adenomas, or hematologic malignancies, underscoring the need for lifelong surveillance.

Functional assays indicate a haploinsufficiency mechanism: TBRS‐derived missense mutations disrupt DNMT3A recruitment to chromatin via impaired recognition of H3K36me2 ([PMID:31485078]), and patient‐derived cells display global and site‐specific hypomethylation with accelerated epigenetic aging ([PMID:31160375]). Mouse models of heterozygous Dnmt3a loss recapitulate overgrowth phenotypes, supporting mechanistic concordance with human disease.

No robust conflicting evidence has been reported; all studies consistently demonstrate that DNMT3A loss‐of‐function or dominant‐negative variants cause TBRS. Additional de novo cases continue to emerge, but the existing data exceed ClinGen scoring thresholds.

Key Take-home: Heterozygous DNMT3A germline variants cause autosomal dominant Tatton-Brown-Rahman syndrome via haploinsufficiency, and genetic testing enables early diagnosis, guides surveillance for cardiovascular and hematologic complications, and informs family planning.

References

• Wellcome open research • 2018 • The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants. PMID:29900417
• Clinical genetics • 2017 • Novel DNMT3A germline mutations are associated with inherited Tatton-Brown-Rahman syndrome. PMID:27701732
• Journal of medical genetics • 2024 • Expanding the genetic and clinical spectrum of Tatton-Brown-Rahman syndrome in a series of 24 French patients. PMID:38937076
• Nature • 2019 • The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape. PMID:31485078
• Genome research • 2019 • Growth disrupting mutations in epigenetic regulatory molecules are associated with abnormalities of epigenetic aging. PMID:31160375

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