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Research paper

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants

Largest TBRS cohort (n=55). 100% intellectual disability, 83% overgrowth (height and/or HC ≥+2 SD), mean birth HC +2.3 SD, 74% joint hypermobility, 67% obesity, 54% hypotonia, 51% behavioral/psychiatric issues, 36% autism, 22% afebrile seizures, 7% regression (mostly adolescent), 33% kyphoscoliosis, one AML. DEE-SWAS/ESES not specifically characterized.

Indexed context

Tatton-Brown K, Zachariou A, Loveday C, et al.

dnmt3atbrsovergrowthintellectual-disabilityautismepilepsychromatinopathy

Markdown path

content/research/papers/2018-tatton-brown-tbrs-clinical-study-55.md

Findings

Largest TBRS cohort (n=55). 100% intellectual disability, 83% overgrowth (height and/or HC ≥+2 SD), mean birth HC +2.3 SD, 74% joint hypermobility, 67% obesity, 54% hypotonia, 51% behavioral/psychiatric issues, 36% autism, 22% afebrile seizures, 7% regression (mostly adolescent), 33% kyphoscoliosis, one AML. DEE-SWAS/ESES not specifically characterized.

Why it may matter for Levi

Anchors DNMT3A/TBRS as a germline chromatinopathy whose phenotype overlaps Levi's on overgrowth, ASD, and seizure axes. Germline coding variants already excluded by Stanford exome, GeneDx WGS, and reanalysis — so TBRS is now a residual epigenetic/mosaic/functional-readout hypothesis, not a missed coding-variant hypothesis.

Paper text

The Tatton-Brown-Rahman Syndrome: A clinical study of 55 individuals with de novo constitutive DNMT3A variants

Tatton-Brown K, Zachariou A, Loveday C, et al. — Wellcome Open Research (2018). https://pmc.ncbi.nlm.nih.gov/articles/PMC5964628/

Findings summary

Largest clinical cohort for DNMT3A-driven Tatton-Brown-Rahman Syndrome (TBRS) at the time (n = 55). Major clinical associations (>80%): intellectual disability (100%; 18% mild, 65% moderate, 16% severe) and overgrowth (83%; height and/or head circumference ≥+2 SD). Mean birth head circumference +2.3 SD, mean birth weight +1.3 SD. Frequent clinical associations (20–80%): joint hypermobility 74%, obesity (weight ≥+2 SD) 67%, hypotonia 54%, behavioural/psychiatric issues 51% (autism spectrum disorder in 36% of the full cohort), kyphoscoliosis 33%, afebrile seizures 22%. Regression was reported in 7%, predominantly in adolescence. Evolving facial gestalt with low-set heavy horizontal eyebrows and prominent upper central incisors. One individual developed acute myeloid leukaemia in teenage years, consistent with the TBRS AML risk later characterized. The paper does not specifically characterize CSWS / ESES / DEE-SWAS EEG phenotypes.

Relevance to Levi

TBRS is a germline DNMT3A overgrowth-plus-intellectual-disability chromatinopathy whose core phenotype overlaps with Levi's in three of the most distinctive axes: symmetric overgrowth from infancy (Levi is 99th percentile height/weight/head circumference since ~12 months), autism-spectrum features, and hypotonia-compatible motor behavior. Afebrile seizures are reported in 22% of the cohort, which is a strong enrichment over the general pediatric population; DEE-SWAS specifically is not characterized in this 2018 cohort but has since been reported (Datta 2026).

Two coding-region germline workups (Stanford trio exome 2025-05-29, GeneDx trio WGS 2026-01-29) plus a targeted reanalysis (GeneDx 2026-04-09) have not identified a pathogenic DNMT3A variant, making a classical germline TBRS coding variant substantially less likely. DNMT3A is one of the epigenetic-regulator genes explicitly named as "substantially excluded" for coding-region germline etiology in the Stanford exome report.

However, the TBRS hypothesis is not fully closed because:

  1. Mosaic DNMT3A variants (not evaluated on blood-based germline trio sequencing) remain untested.
  2. Deep-intronic, regulatory, or structural DNMT3A variants at the locus are imperfectly detected by standard short-read WGS interpretation pipelines.
  3. A functional readout — genome-wide DNA methylation / episignature testing — has not been performed. DNMT3A has a robust, essentially 100% sensitive hypomethylation episignature in blood (see Levy 2022; van der Sanden 2023). An EpiSign panel would directly functionally test for TBRS regardless of whether the causal variant was captured by WGS.

This keeps TBRS as the single most testable residual genetic hypothesis that is not already closed by the current workup, despite its residual probability being low.

Provenance