Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1

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. Althou...

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Published in:European journal of human genetics : EJHG 2015-08, Vol.23 (8), p.1010-1018
Main Authors: El Khattabi, Laïla, Guimiot, Fabien, Pipiras, Eva, Andrieux, Joris, Baumann, Clarisse, Bouquillon, Sonia, Delezoide, Anne-Lise, Delobel, Bruno, Demurger, Florence, Dessuant, Hélène, Drunat, Séverine, Dubourg, Christelle, Dupont, Céline, Faivre, Laurence, Holder-Espinasse, Muriel, Jaillard, Sylvie, Journel, Hubert, Lyonnet, Stanislas, Malan, Valérie, Masurel, Alice, Marle, Nathalie, Missirian, Chantal, Moerman, Alexandre, Moncla, Anne, Odent, Sylvie, Palumbo, Orazio, Palumbo, Pietro, Ravel, Aimé, Romana, Serge, Tabet, Anne-Claude, Valduga, Mylène, Vermelle, Marie, Carella, Massimo, Dupont, Jean-Michel, Verloes, Alain, Benzacken, Brigitte, Delahaye, Andrée
Format: Article
Language:English
Subjects:
Aborted Fetus
Adolescent
Adult
Basic Helix-Loop-Helix Transcription Factors - genetics
Cell migration
Cerebellum
Child
Child, Preschool
Chromosome 2
Chromosome 6
Chromosomes
Chromosomes, Human, Pair 6 - genetics
Clonal deletion
Comparative Genomic Hybridization
Female
Fetuses
Gene polymorphism
Genes
Genetic Association Studies
Genetic variability
Genetics
Genotype & phenotype
Haploinsufficiency
Humans
Hybridization
Infant
Leukocyte migration
Life Sciences
Male
Obesity
Obesity - complications
Obesity - genetics
Obesity - pathology
Patients
Penetrance
Phenotypes
Polymorphism, Single Nucleotide
Prader-Willi syndrome
Prader-Willi Syndrome - complications
Prader-Willi Syndrome - genetics
Prader-Willi Syndrome - pathology
Pregnancy
Repressor Proteins - genetics
Rodents
Single-nucleotide polymorphism
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Summary: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.
ISSN:1018-4813
1476-5438
DOI:10.1038/ejhg.2014.230