Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.

TitleMonoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.
Publication TypeJournal Article
Year of Publication2023
AuthorsCalame, DG, Guo, T, Wang, C, Garrett, L, Jolly, A, Dawood, M, Kurolap, A, Henig, NZunz, Fatih, JM, Herman, I, Du, H, Mitani, T, Becker, L, Rathkolb, B, Gerlini, R, Seisenberger, C, Marschall, S, Hunter, JV, Gerard, A, Heidlebaugh, A, Challman, T, Spillmann, RC, Jhangiani, SN, Coban-Akdemir, Z, Lalani, S, Liu, L, Revah-Politi, A, Iglesias, A, Guzman, E, Baugh, E, Boddaert, N, Rondeau, S, Ormieres, C, Barcia, G, Tan, QKG, Thiffault, I, Pastinen, T, Sheikh, K, Biliciler, S, Mei, D, Melani, F, Shashi, V, Yaron, Y, Steele, M, Wakeling, E, Østergaard, E, Nazaryan-Petersen, L, Millan, F, Santiago-Sim, T, Thevenon, J, Bruel, A-L, Thauvin-Robinet, C, Popp, D, Platzer, K, Gawlinski, P, Wiszniewski, W, Marafi, D, Pehlivan, D, Posey, JE, Gibbs, RA, Gailus-Durner, V, Guerrini, R, Fuchs, H, de Angelis, MHrabě, Hölter, SM, Cheung, H-H, Gu, S, Lupski, JR
Corporate AuthorsUndiagnosed Diseases Network
JournalAm J Hum Genet
Date Published2023 Aug 03
KeywordsAnimals, Cell Line, Charcot-Marie-Tooth Disease, DEAD-box RNA Helicases, Dichlorodiphenyl Dichloroethylene, DNA Helicases, Humans, Mammals, Mice, Neoplasm Proteins, Neurodevelopmental Disorders

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9 mice exhibited hypoactivity in novel environments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.

Alternate JournalAm J Hum Genet
PubMed ID37467750
PubMed Central IDPMC10432148
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
K23 NS125126 / NS / NINDS NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
U01 HG007672 / HG / NHGRI NIH HHS / United States
T32 NS043124 / NS / NINDS NIH HHS / United States
T32 AI007526 / AI / NIAID NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P50 HD103555 / HD / NICHD NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States

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