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J Med Genet. 2014 Aug;51(8):512-7. doi: 10.1136/jmedgenet-2014-102402. Epub 2014 May 22.

Mutations in SETD2 cause a novel overgrowth condition.

Author information

EA7331, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France Service de Biochimie et de Génétique Moléculaire, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France.
Service d'Histo-Embryo-Cytogénétique, Université Paris Descartes, Sorbonne Paris Cité, Hôpital Necker-Enfants Malades, Paris, France.
Service de Génétique Médicale, CHU Estaing, Clermont-Ferrand, France.
Université de Rennes 1, CNRS UMR6290, Service de Génétique Clinique, CHU Hôpital Sud, Rennes, France.
Service de Génétique Médicale, CHU Hôpital l'Archet 2, Nice, France.
Service de Génétique Médicale, CHU de Bordeaux et EA4576, Université de Bordeaux, Bordeaux, France.
Service de Génétique, CHU de Saint-Etienne, hôpital Nord, Saint-Etienne, France.
INSERM UMR_1163, Département de génétique, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.



Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. NSD1 and EZH2 are both histone-modifying enzymes. These two epigenetic writers catalyse two specific post-translational modifications of histones: methylation of histone 3 lysine 36 (H3K36) and lysine 27 (H3K27). We postulated that mutations in writers of these two chromatin marks could cause overgrowth conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or EZH2 abnormalities.


We analysed the coding sequences of 14 H3K27 methylation-related genes and eight H3K36 methylation-related genes using a targeted next-generation sequencing approach in three Sotos, 11 'Sotos-like' and two Weaver syndrome patients.


We identified two heterozygous mutations in the SETD2 gene in two patients with 'Sotos-like' syndrome: one missense p.Leu1815Trp de novo mutation in a boy and one nonsense p.Gln274* mutation in an adopted girl. SETD2 is non-redundantly responsible for H3K36 trimethylation. The two probands shared similar clinical features, including postnatal overgrowth, macrocephaly, obesity, speech delay and advanced carpal ossification.


Our results illustrate the power of targeted next-generation sequencing to identify rare disease-causing variants. We provide a compelling argument for Sotos and Sotos-like syndromes as epigenetic diseases caused by loss-of-function mutations of epigenetic writers of the H3K36 histone mark.


Clinical genetics; Developmental; Molecular genetics

[Indexed for MEDLINE]

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