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

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.

Keywords: DNMT3A; Tatton–Brown–Rahman syndrome; acute myeloid leukemia; intellectual disability; macrocephaly.

Figure 1

General Face2Gene page, with the Tatton–Brown–Rahman Syndrome in third place with a low gestalt score (A). Comparison of heat maps of patient’s image on the left and the reported proband on the right in the Face2Gene system (B). The phenotype of the reported proband, with macrocephaly, mild facial dysmorphism, and strabismus (C).

Figure 2

The pedigree of the reported family (A) and the results of Sanger sequencing confirming the de novo status of the variant in the DNMT3A gene (B).