RT Journal Article
SR Electronic
T1 <em>SETD2</em> and <em>DNMT3A</em> screen in the Sotos-like syndrome French cohort
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 743
OP 751
DO 10.1136/jmedgenet-2015-103638
VO 53
IS 11
A1 Camille Tlemsani
A1 Armelle Luscan
A1 Nicolas Leulliot
A1 Eric Bieth
A1 Alexandra Afenjar
A1 Geneviève Baujat
A1 Martine Doco-Fenzy
A1 Alice Goldenberg
A1 Didier Lacombe
A1 Laetitia Lambert
A1 Sylvie Odent
A1 Jérôme Pasche
A1 Sabine Sigaudy
A1 Alexandre Buffet
A1 Céline Violle-Poirsier
A1 Audrey Briand-Suleau
A1 Ingrid Laurendeau
A1 Magali Chin
A1 Pascale Saugier-Veber
A1 Dominique Vidaud
A1 Valérie Cormier-Daire
A1 Michel Vidaud
A1 Eric Pasmant
A1 Lydie Burglen
YR 2016
UL http://jmg.bmj.com/content/53/11/743.abstract
AB Background Heterozygous NSD1 mutations were identified in 60%–90% of patients with Sotos syndrome. Recently, mutations of the SETD2 and DNMT3A genes were identified in patients exhibiting only some Sotos syndrome features. Both NSD1 and SETD2 genes encode epigenetic ‘writer’ proteins that catalyse methylation of histone 3 lysine 36 (H3K36me). The DNMT3A gene encodes an epigenetic ‘reader’ protein of the H3K36me chromatin mark.Methods We aimed at confirming the implication of DNMT3A and SETD2 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 NSD1 mutation, from a French cohort.Results Six unreported heterozygous likely pathogenic variants in DNMT3A were identified in seven patients: two nonsense variants and four de novo missense variants. One de novo unreported heterozygous frameshift variant was identified in SETD2 in one patient. All the four DNMT3A missense variants affected DNMT3A functional domains, suggesting a potential deleterious impact. DNMT3A-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 SETD2 mutations remains to be described more precisely. The p.Arg882Cys missense de novo constitutional DNMT3A variant found in two patients is the most frequent DNMT3A somatic mutation in acute leukaemia.Conclusions 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 SETD2 and DNMT3A in intellectual deficiency without overgrowth.