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Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.


ABSTRACT: PURPOSE:CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome. METHODS:We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome. RESULTS:Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. The remaining eight (28.6%) individuals were not found to have pathogenic variants by WES. CONCLUSION:These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.

SUBMITTER: Moccia A 

PROVIDER: S-EPMC6034995 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.

Moccia Amanda A   Srivastava Anshika A   Skidmore Jennifer M JM   Bernat John A JA   Wheeler Marsha M   Chong Jessica X JX   Nickerson Deborah D   Bamshad Michael M   Hefner Margaret A MA   Martin Donna M DM   Bielas Stephanie L SL  

Genetics in medicine : official journal of the American College of Medical Genetics 20180104 9


<h4>Purpose</h4>CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagn  ...[more]

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