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

1 Service de Biologie du Développement
2 Service Histologie-embryologie-cytogénétique
3 Laboratoire de Génétique Clinique
4 Département de Génétique Médicale
5 SYRTE - Systèmes de Référence Temps Espace
6 Service de Biologie du Développement
7 Centre de Génétique Chromosomique
8 Service de Cytogénétique et de Biologie Cellulaire
9 Département de génétique
10 IGDR - Institut de Génétique et Développement de Rennes
11 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
12 Service de génétique clinique
13 Service de Génétique Médicale [CHU Necker]
14 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
15 Service de génétique
16 Département de génétique médicale [Hôpital de la Timone - APHM]
17 Service de Génétique clinique
18 Laboratoire de Génétique Chromosomique
19 Centre de Référence " Anomalies du Développement et Syndromes Malformatifs Sud - Est PACA "
20 PARTHENOPE - Università degli Studi di Napoli “Parthenope” = University of Naples
21 EMI0210 - INSERM EMI0210
22 Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]
23 Instituto di Ricovero e Cura a Carattere Scientifico
24 Physiopathologie et neuroprotection des atteintes du cerveau en développement
25 AP HP, Reprod Biol Unit CECOS

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.

Domains: Life Sciences [q-bio]

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, 2015, 23 (8), pp.1010-1018. ⟨10.1038/ejhg.2014.230⟩. ⟨hal-01116591⟩