期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 105, 期 2, 页码 302-316出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2019.06.001
关键词
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资金
- National Human Genome Research Institute (NHGRI) [UM1 HG006542, UM1 HG006493]
- National Heart, Lung, and Blood Institute (NHLBI)
- University of Washington Center for Mendelian Genomics [R01 NS058529, R35 NS105078]
- National Institute of Neurological Disorders and Stroke (NINDS)
- NHGRI [K08 HG008986]
- Telethon Undiagnosed Diseases Program [GSP15001]
- Telethon Foundation
- Aicardi Syndrome Foundation [2T32NS043124-16]
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK088767]
- Werner Otto Stiftung [K12 DK083014]
- German Research Foundation (DFG) [LE 4223/1]
- Common Fund of the Office of the Director of the National Institutes of Health
- National Cancer Institute, NHGRI
- NHLBI
- National Institute on Drug Abuse
- National Institute of Mental Health
- NINDS
Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.
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