Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.

TitleGenetic analysis of CHARGE syndrome identifies overlapping molecular biology.
Publication TypeJournal Article
Year of Publication2018
AuthorsMoccia, A, Srivastava, A, Skidmore, JM, Bernat, JA, Wheeler, M, Chong, JX, Nickerson, D, Bamshad, M, Hefner, MA, Martin, DM, Bielas, SL
JournalGenet Med
Date Published2018 09
KeywordsAdolescent, Adult, Carrier Proteins, CHARGE Syndrome, Child, Child, Preschool, Cohort Studies, DNA Helicases, DNA-Binding Proteins, E1A-Associated p300 Protein, Epigenesis, Genetic, Female, Genetic Testing, Humans, Infant, Male, Mutation, Neoplasm Proteins, Phenotype, Repressor Proteins, RNA Splicing Factors

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.

Alternate JournalGenet. Med.
PubMed ID29300383
PubMed Central IDPMC6034995
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
T32 HL007828 / HL / NHLBI NIH HHS / United States
R01 DC009410 / DC / NIDCD NIH HHS / United States
R00 HD069624 / HD / NICHD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
T32 GM007544 / GM / NIGMS NIH HHS / United States
R01 DC014456 / DC / NIDCD NIH HHS / United States