<i>SETD2</i> and <i>DNMT3A</i> screen in the Sotos-like syndrome French cohort.

Abstract

Heterozygous <i>NSD1</i> mutations were identified in 60%-90% of patients with Sotos syndrome. Recently, mutations of the <i>SETD2</i> and <i>DNMT3A</i> genes were identified in patients exhibiting only some Sotos syndrome features. Both <i>NSD1</i> and <i>SETD2</i> genes encode epigenetic 'writer' proteins that catalyse methylation of histone 3 lysine 36 (H3K36me). The <i>DNMT3A</i> gene encodes an epigenetic 'reader' protein of the H3K36me chromatin mark. We aimed at confirming the implication of <i>DNMT3A</i> and <i>SETD2</i> mutations in an overgrowth phenotype, through a comprehensive targeted-next generation sequencing (NGS) screening in 210 well-phenotyped index cases with a Sotos-like phenotype and no <i>NSD1</i> mutation, from a French cohort. Six unreported heterozygous likely pathogenic variants in <i>DNMT3A</i> were identified in seven patients: two nonsense variants and four de novo missense variants. One de novo unreported heterozygous frameshift variant was identified in <i>SETD2</i> in one patient. All the four DNMT3A missense variants affected DNMT3A functional domains, suggesting a potential deleterious impact. <i>DNMT3A</i>-mutated index cases shared similar clinical features including overgrowth phenotype characterised by postnatal tall stature (≥+2SD), macrocephaly (≥+2SD), overweight or obesity at older age, intellectual deficiency and minor facial features. The phenotype associated with <i>SETD2</i> mutations remains to be described more precisely. The p.Arg882Cys missense de novo constitutional DNMT3A variant found in two patients is the most frequent <i>DNMT3A</i> somatic mutation in acute leukaemia. Our results illustrate the power of targeted NGS to identify rare disease-causing variants. These observations provided evidence for a unifying mechanism (disruption of apposition and reading of the epigenetic chromatin mark H3K36me) that causes an overgrowth syndrome phenotype. Further studies are needed in order to assess the role of <i>SETD2</i> and <i>DNMT3A</i> in intellectual deficiency without overgrowth.