Paralog Studies Augment Gene Discovery: DDX and DHX Genes

PubMedID: 31256877Members 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. © 2019 American Society of Human GeneticsNational Heart, Lung, and Blood Institute Aicardi Syndrome Foundation: 2T32NS043124-16 National Institute on Drug Abuse National Institute of Diabetes and Digestive and Kidney Diseases: K12 DK083014 National Heart, Lung, and Blood Institute Fondazione Telethon National Institute of Neurological Disorders and Stroke: U54-HG003273 GSP15001 Deutsche Forschungsgemeinschaft California Department of Fish and Game: LE 4223/1 National Human Genome Research Institute National Institutes of Health: K08 HG008986, DK088767 National Cancer Institute R01 NS058529, R35 NS105078 National Institute of Mental Health National Institute of Neurological Disorders and StrokeThis work was supported in part by grants UM1 HG006542 (J.R.L) and UM1 HG006493 (M.B.) from the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI) to the Baylor Hopkins Center for Mendelian Genomics and the University of Washington Center for Mendelian Genomics, R01 NS058529 and R35 NS105078 (J.R.L.) from the National Institute of Neurological Disorders and Stroke (NINDS), U54-HG003273 (R.A.G.) from NHGRI , and Telethon Undiagnosed Diseases Program (TUDP) GSP15001 (N.B.-P.) from the Telethon Foundation , and also by the Aicardi Syndrome Foundation. I.P. was supported by 2T32NS043124-16 through the National Institutes of Health . J.E.P. was supported by NHGRI K08 HG008986 . F.H. was supported by the National Institutes of Health ( DK088767 ). M.R.B. was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K12 DK083014 . D.L was supported by the Werner Otto Stiftung and the German Research Foundation ( DFG; LE 4223/1 ). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health , and by the National Cancer Institute , NHGRI , NHLBI , the National Institute on Drug Abuse , the National Institute of Mental Health , and NINDS . The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 10/29/18. The authors would like to thank Hans-Jurgen Kreienkamp for the help in identifying helicase core motifs and the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about