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Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.

Laïla El Khattabi Fabien Guimiot 1 Eva Pipiras 2 Joris Andrieux 3 Clarisse Baumann 4 Sonia Bouquillon 5 Anne-Lise Delezoide 6 Bruno Delobel 7 Florence Demurger 8 Hélène Dessuant Séverine Drunat 9 Christelle Dubourg 10 Céline Dupont Laurence Faivre 11 Muriel Holder-Espinasse 12 Sylvie Jaillard 8 Hubert Journel Stanislas Lyonnet 13, 14 Valérie Malan 14 Alice Masurel 15 Nathalie Marle Chantal Missirian 16 Alexandre Moerman 17 Anne Moncla 18, 19 Sylvie Odent 10 Orazio Palumbo Pietro Palumbo 20 Aimé Ravel Serge Romana 21, 22 Anne-Claude Tabet 9 Mylène Valduga Marie Vermelle Massimo Carella 23 Jean-Michel Dupont Alain Verloes 24, 9 Brigitte Benzacken 25 Andrée Delahaye
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.
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Submitted on : Friday, February 13, 2015 - 4:37:17 PM
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Laïla El Khattabi, Fabien Guimiot, Eva Pipiras, Joris Andrieux, Clarisse Baumann, et al.. Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.. European Journal of Human Genetics, Nature Publishing Group, 2015, 23 (8), pp.1010-1018. ⟨10.1038/ejhg.2014.230⟩. ⟨hal-01116591⟩



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