2. Academic Validation
  3. SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort

SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort

  • J Med Genet. 2016 Nov;53(11):743-751. doi: 10.1136/jmedgenet-2015-103638.
Camille Tlemsani 1 2,  Armelle Luscan 1 2,  Nicolas Leulliot 3,  Eric Bieth 4,  Alexandra Afenjar 5,  Geneviève Baujat 6,  Martine Doco-Fenzy 7,  Alice Goldenberg 8,  Didier Lacombe 9,  Laetitia Lambert 10,  Sylvie Odent 11,  Jérôme Pasche 12,  Sabine Sigaudy 13,  Alexandre Buffet 14,  Céline Violle-Poirsier 15,  Audrey Briand-Suleau 1,  Ingrid Laurendeau 2,  Magali Chin 2,  Pascale Saugier-Veber 8 16,  Dominique Vidaud 1 2,  Valérie Cormier-Daire 5,  Michel Vidaud 1 2,  Eric Pasmant 1 2,  Lydie Burglen 5 17
Affiliations

Affiliations

  • 1 Service de Génétique et Biologie Moléculaires, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, AP-HP, Paris, France.
  • 2 EA7331, Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • 3 Faculté de Pharmacie, Laboratoire de Cristallographie et RMN Biologiques-CNRS UMR-8015, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • 4 Service de Génétique, Hôpital Purpan, Toulouse, France.
  • 5 Département de Génétique, Centre de référence des anomalies du développement et syndromes malformatifs, Hôpital Trousseau, AP-HP, Paris, France.
  • 6 INSERM UMR_1163, Département de Génétique, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
  • 7 Service de génétique HMB CHU Reims, EA 3801, SFR CAPSANTE, Reims, France.
  • 8 Service de Génétique, Centre Normand de Génomique Médicale et Médecine personnalisée, CHU de Rouen, Rouen, France.
  • 9 Service de Génétique, CHU Bordeaux, Bordeaux, France.
  • 10 Service de Génétique, CHU, Nancy, France.
  • 11 Service de Génétique, CHU, Rennes, France.
  • 12 Service de Pédiatrie, Centre Hospitalier de Polynésie française, Papeete, Tahiti, France.
  • 13 Service de Génétique, CHU de Marseille-Hôpital de la Timone, Marseille, France.
  • 14 Service d'Endocrinologie, Maladies Métaboliques, Nutrition, Hôpital Larrey, Toulouse, France.
  • 15 Département de Génétique, CHU de Reims, Reims, France.
  • 16 Inserm U1079, Université de Rouen, IRIB, Rouen, France.
  • 17 INSERM UMR_1141, Paris, France.
PMID: 27317772 DOI: 10.1136/jmedgenet-2015-103638
Abstract

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.

Keywords

DNMT3A; H3K36me3; Overgrowth; SETD2; Sotos syndrome.

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