SETD2 related overgrowth syndrome: Presentation of four new patients and review of the literature

Pauline Marzin, Sophie Rondeau, Kimberly A. Aldinger, Jean Luc Alessandri, Bertrand Isidor, Delphine Heron, Boris Keren, William B. Dobyns, Valérie Cormier-Daire

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The common genes responsible for overgrowth syndromes play key roles in regulating transcription through histone modification and chromatin modeling. The SETD2 gene encoding a H3K36 trimethyltransferase is implicated in Sotos-like syndrome. This syndrome is characterized by postnatal overgrowth, macrocephaly, obesity, speech delay, and advanced carpal ossification. We report four new patients with constitutional SETD2 mutations and review nine earlier reported patients. Almost all patients presented with macrocephaly associated with advanced stature and obesity in half of the cases. In addition to these principal manifestations, neurodevelopmental disorders are common such as intellectual disability (83%), autism spectrum disorders (89%), and behavioral difficulties (100%) with aggressive outbursts (83%). A variety of features such as joint hypermobility (29%), hirsutism (33%), and naevi (50%) were also reported. Constitutional SETD2 mutations are intragenic loss-of-function variants with truncating (69%) and missense (31%) mutations. Functional studies are necessary to improve understanding of the pathogenicity of some missense SETD2 mutations.

Original languageEnglish (US)
Pages (from-to)509-518
Number of pages10
JournalAmerican Journal of Medical Genetics, Part C: Seminars in Medical Genetics
Volume181
Issue number4
DOIs
StatePublished - Dec 1 2019
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by NIH National Institute of Neurological Diseases and Stroke (R01NS050375) and the Dandy-Walker Alliance to WBD. The authors thank Julien Buratti for his help in exome analysis and Farah Lawrence-Wilde for her thorough rereading of this article.

Funding Information:
This work was supported by NIH National Institute of Neurological Diseases and Stroke (R01NS050375) and the Dandy‐Walker Alliance to WBD. The authors thank Julien Buratti for his help in exome analysis and Farah Lawrence‐Wilde for her thorough rereading of this article.

Publisher Copyright:
© 2019 Wiley Periodicals, Inc.

Keywords

  • SETD2
  • autism spectrum disorder
  • histone methyltransferases
  • overgrowth

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