Journal article
Genetic analysis of CHARGE syndrome identifies overlapping molecular biology
Genetics in medicine, Vol.20(9), pp.1022-1029
09/2018
DOI: 10.1038/gim.2017.233
PMCID: PMC6034995
PMID: 29300383
Abstract
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.
We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome.
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.
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.
Details
- Title: Subtitle
- Genetic analysis of CHARGE syndrome identifies overlapping molecular biology
- Creators
- Amanda Moccia - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USAAnshika Srivastava - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USAJennifer M Skidmore - Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USAJohn A Bernat - Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USAMarsha Wheeler - University of Washington Center for Mendelian Genomics, University of Washington, Seattle, Washington, USAJessica X Chong - University of Washington Center for Mendelian Genomics, University of Washington, Seattle, Washington, USADeborah Nickerson - University of Washington Center for Mendelian Genomics, University of Washington, Seattle, Washington, USAMichael Bamshad - University of Washington Center for Mendelian Genomics, University of Washington, Seattle, Washington, USAMargaret A Hefner - Department of Pediatrics, Saint Louis University School of Medicine, St. Louis, Missouri, USADonna M Martin - Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA. donnamm@umich.eduStephanie L Bielas - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA. sbielas@umich.edu
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.20(9), pp.1022-1029
- DOI
- 10.1038/gim.2017.233
- PMID
- 29300383
- PMCID
- PMC6034995
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Grant note
- U54 HG006493 / NHGRI NIH HHS UM1 HG006493 / NHGRI NIH HHS R00 HD069624 / NICHD NIH HHS R01 DC014456 / NIDCD NIH HHS T32 HL007828 / NHLBI NIH HHS T32 GM007544 / NIGMS NIH HHS R01 DC009410 / NIDCD NIH HHS
- Language
- English
- Date published
- 09/2018
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984093480802771
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