# Clinical Case of Mild Tatton–Brown–Rahman Syndrome Caused by a Nonsense Variant in DNMT3A Gene

## TL;DR

A 10-year-old boy with a rare genetic disorder caused by a new mutation in the DNMT3A gene shows mild symptoms, expanding the known range of this condition.

## Contribution

This is the first report of a recurrent nonsense variant in DNMT3A, suggesting a mutational hot-spot and highlighting a milder clinical presentation.

## Key findings

- A de novo nonsense variant in DNMT3A (c.1443C>A, p.Tyr481Ter) was identified in a patient with mild Tatton–Brown–Rahman syndrome.
- The case expands the phenotypic spectrum of the syndrome, showing milder symptoms than typically reported.
- The variant is a potential mutational hot-spot, as it is recurrent and not found in the patient's parents.

## Abstract

Tatton–Brown–Rahman syndrome is a rare autosomal dominant hereditary disease caused by pathogenic variants in the DNMT3A gene, which is an important participant in epigenetic regulation, especially during embryonic development, and is highly expressed in all tissues. The main features of the syndrome are high growth, macrocephaly, intellectual disability, and facial dysmorphic features. We present a clinical case of Tatton–Brown–Rahman syndrome in a ten-year-old boy with macrocephaly with learning difficulties, progressive eye impairment, and fatigue suspected by a deep learning-based diagnosis assistance system, Face2Gene. The proband underwent whole-exome sequencing, which revealed a recurrent nonsense variant in the 12th exon of the DNMT3A, leading to the formation of a premature stop codon—NM_022552.5:c.1443C>A (p.Tyr481Ter), in a heterozygous state. This variant was not found in parents, confirming its de novo status. The patient case described here contributes to the understanding of the clinical diversity of Tatton–Brown–Raman syndrome with a mild clinical presentation that expands the phenotypic spectrum of the syndrome. We report the first recurrent nonsense variant in the DNMT3A gene, suggesting a mutational hot-spot. Differential diagnoses of this syndrome with Sotos syndrome, Weaver syndrome, and Cowden syndrome, as well as molecular confirmation, are extremely important, since the presence of certain types of pathogenic variants in the DNMT3A gene significantly increases the risk of developing acute myeloid leukemia.