TY - JOUR
T1 - Paralog Studies Augment Gene Discovery
T2 - DDX and DHX Genes
AU - University of Washington Center for Mendelian Genomics, Baylor-Hopkins Center for Mendelian Genomics, Telethon Undiagnosed Diseases Program
AU - Paine, Ingrid
AU - Posey, Jennifer E.
AU - Grochowski, Christopher M.
AU - Jhangiani, Shalini N.
AU - Rosenheck, S.
AU - Kleyner, Robert
AU - Marmorale, Taylor
AU - Yoon, Margaret
AU - Wang, Kai
AU - Robison, Reid
AU - Cappuccio, Gerarda
AU - Pinelli, Michele
AU - Magli, Adriano
AU - Coban Akdemir, Zeynep
AU - Hui, Joannie
AU - Yeung, Wai Lan
AU - Wong, Bibiana K.Y.
AU - Ortega, L.
AU - Bekheirnia, Mir Reza
AU - Bierhals, Tatjana
AU - Hempel, Maja
AU - Johannsen, Jessika
AU - Santer, René
AU - Aktas, D.
AU - Alikasifoglu, Mehmet
AU - Bozdogan, Sevcan
AU - Aydin, H.
AU - Karaca, E.
AU - Bayram, Y.
AU - Ityel, H.
AU - Dorschner, Michael
AU - White, Janson J.
AU - Wilichowski, Ekkehard
AU - Wortmann, Saskia B.
AU - Casella, Erasmo B.
AU - Kitajima, Joao Paulo
AU - Kok, Fernando
AU - Monteiro, Fabiola
AU - Muzny, Donna M.
AU - Bamshad, Michael
AU - Gibbs, Richard A.
AU - Sutton, V. Reid
AU - Van Esch, H.
AU - Brunetti-Pierri, Nicola
AU - Hildebrandt, Friedhelm
AU - Brautbar, A.
AU - Van den Veyver, Ignatia B.
AU - Glass, Ian
AU - Lessel, D.
AU - Lyon, Gholson J.
N1 - Publisher Copyright:
© 2019 American Society of Human Genetics
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
KW - DExD/H-box RNA helicase family
KW - developmental delay
KW - human paralogs
KW - intellectual disability
UR - http://www.scopus.com/inward/record.url?scp=85069846729&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.06.001
DO - 10.1016/j.ajhg.2019.06.001
M3 - Article
C2 - 31256877
AN - SCOPUS:85069846729
SN - 0002-9297
VL - 105
SP - 302
EP - 316
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -