Dataset Information

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

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.

SUBMITTER: El Khattabi L

PROVIDER: S-EPMC4795105 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

El Khattabi Laïla L Guimiot Fabien F Pipiras Eva E Andrieux Joris J Baumann Clarisse C Bouquillon Sonia S Delezoide Anne-Lise AL Delobel Bruno B Demurger Florence F Dessuant Hélène H Drunat Séverine S Dubourg Christelle C Dupont Céline C Faivre Laurence L Holder-Espinasse Muriel M Jaillard Sylvie S Journel Hubert H Lyonnet Stanislas S Malan Valérie V Masurel Alice A Marle Nathalie N Missirian Chantal C Moerman Alexandre A Moncla Anne A Odent Sylvie S Palumbo Orazio O Palumbo Pietro P Ravel Aimé A Romana Serge S Tabet Anne-Claude AC Valduga Mylène M Vermelle Marie M Carella Massimo M Dupont Jean-Michel JM Verloes Alain A Benzacken Brigitte B Delahaye Andrée A

European journal of human genetics : EJHG 20141105 8

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 de ...[more]

PMID: 25351778

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Project description:BACKGROUND:Chromosome 22q11.2 is susceptible to genomic rearrangements and the most frequently reported involve deletions and duplications between low copy repeats LCR22A to LCR22D. Atypical nested deletions and duplications are rarer and can provide a valuable opportunity to investigate the dosage effects of a smaller subset of genes within the 22q11.2 genomic disorder region. METHODS:We describe thirteen individuals from six families, each with atypical nested duplications within the central 22q11.2 region between LCR22B and LCR22D. We then compared the molecular and clinical data for patients from this study and the few reported atypical duplication cases, to the cases with larger typical duplications between LCR22A and LCR22D. Further, we analyzed genes with the nested region to identify candidates highly enriched in human brain tissues. RESULTS:We observed that atypical nested duplications are heterogeneous in size, often familial, and associated with incomplete penetrance and highly variable clinical expressivity. We found that the nested atypical duplications are a possible risk factor for neurodevelopmental phenotypes, particularly for autism spectrum disorder (ASD), speech and language delay, and behavioral abnormalities. In addition, we analyzed genes within the nested region between LCR22B and LCR22D to identify nine genes (ZNF74, KLHL22, MED15, PI4KA, SERPIND1, CRKL, AIFM3, SLC7A4, and BCRP2) with enriched expression in the nervous system, each with unique spatiotemporal patterns in fetal and adult brain tissues. Interestingly, PI4KA is prominently expressed in the brain, and this gene is included either partially or completely in all of our subjects. CONCLUSION:Our findings confirm variable expressivity and incomplete penetrance for atypical nested 22q11.2 duplications and identify genes such as PI4KA to be directly relevant to brain development and disorder. We conclude that further work is needed to elucidate the basis of variable neurodevelopmental phenotypes and to exclude the presence of a second disorder. Our findings contribute to the genotype-phenotype data for atypical nested 22q11.2 duplications, with implications for genetic counseling.

Dataset Information

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

Publications

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

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