Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

Laïla El Khattabi, Fabien Guimiot, Eva Pipiras, Joris Andrieux, Clarisse Baumann, Sonia Bouquillon, Anne Lise Delezoide, Bruno Delobel, Florence Demurger, Hélène Dessuant, Séverine Drunat, Christelle Dubourg, Céline Dupont, Laurence Faivre, Muriel Holder-Espinasse, Sylvie Jaillard, Hubert Journel, Stanislas Lyonnet, Valérie Malan, Alice MasurelNathalie Marle, Chantal Missirian, Alexandre Moerman, Anne Moncla, Sylvie Odent, Orazio Palumbo, Pietro Palumbo, Aimé Ravel, Serge Romana, Anne Claude Tabet, Mylène Valduga, Marie Vermelle, Massimo Carella, Jean Michel Dupont, Alain Verloes, Brigitte Benzacken, Andrée Delahaye

Research output: Contribution to journalArticlepeer-review

Abstract

6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.

Original languageEnglish
Pages (from-to)1010-1018
Number of pages9
JournalEuropean Journal of Human Genetics
Volume23
Issue number8
DOIs
Publication statusPublished - Aug 21 2015

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

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