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Paine, I.* ; Posey, J.E.* ; Grochowski, C.M.* ; Jhangiani, S.N.* ; Rosenheck, S.* ; Kleyner, R.* ; Marmorale, T.* ; Yoon, M.* ; Wang, K.* ; Robison, R.* ; Cappuccio, G.* ; Pinelli, M.* ; Magli, A.* ; Coban Akdemir, Z.* ; Hui, J.* ; Yeung, W.L.* ; Wong, B.K.Y.* ; Ortega, L.* ; Bekheirnia, M.R.* ; Bierhals, T.* ; Hempel, M.* ; Johannsen, J.* ; Santer, R.* ; Aktas, D.* ; Alikasifoglu, M.* ; Bozdogan, S.* ; Aydin, H.* ; Karaca, E.* ; Bayram, Y.* ; Ityel, H.* ; Dorschner, M.* ; White, J.J.* ; Wilichowski, E.* ; Wortmann, S.B. ; Casella, E.B.* ; Kitajima, J.P.* ; Kok, F.* ; Monteiro, F.* ; Muzny, D.M.* ; Bamshad, M.* ; Gibbs, R.A.* ; Sutton, V.R.* ; van Esch, H.* ; Brunetti-Pierri, N.* ; Hildebrandt, F.* ; Brautbar, A.* ; Van den Veyver, I.B.* ; Glass, I.* ; Lessel, D.* ; Lyon, G.J.* ; Lupski, J.R.*

Paralog studies augment gene discovery: DDX and DHX genes.

Am. J. Hum. Genet. 105, 302-316 (2019)
Publ. Version/Full Text Preprint Research data DOI
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Developmental Delay ; Dexd/h-box Rna Helicase Family ; Human Paralogs ; Intellectual Disability; Intellectual Disability; De-novo; Common-cause; Mutations; Identification; Protein; Variants; Mutants; Nmd
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Quellenangaben Volume: 105, Issue: 2, Pages: 302-316 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place New York, NY
Reviewing status Peer reviewed