Paralog Studies Augment Gene Discovery: DDX and DHX Genes

  • Ingrid Paine
  • Jennifer E Posey
  • Christopher M Grochowski
  • Shalini N Jhangiani
  • Sarah Rosenheck
  • Robert Kleyner
  • Taylor Marmorale
  • Margaret Yoon
  • Kai Wang
  • Reid Robison
  • Gerarda Cappuccio
  • Michele Pinelli
  • Adriano Magli
  • Zeynep Coban Akdemir
  • Joannie Hui
  • Wai Lan Yeung
  • Bibiana K Y Wong
  • Lucia Ortega
  • Mir Reza Bekheirnia
  • Tatjana Bierhals
  • Maja Hempel
  • Jessika Johannsen
  • René Santer
  • Dilek Aktas
  • Mehmet Alikasifoglu
  • Sevcan Bozdogan
  • Hatip Aydin
  • Ender Karaca
  • Yavuz Bayram
  • Hadas Ityel
  • Michael Dorschner
  • Janson J White
  • Ekkehard Wilichowski
  • Saskia B Wortmann
  • Erasmo B Casella
  • Joao Paulo Kitajima
  • Fernando Kok
  • Fabiola Monteiro
  • Donna M Muzny
  • Michael Bamshad
  • Richard A Gibbs
  • V Reid Sutton
  • University of Washington Center for Mendelian Genomics, Baylor-Hopkins Center for Mendelian Genomics, Telethon Undiagnosed Diseases Program
  • Hilde Van Esch
  • Nicola Brunetti-Pierri
  • Friedhelm Hildebrandt
  • Ariel Brautbar
  • Ignatia B Van den Veyver
  • Ian Glass
  • Davor Lessel
  • Gholson J Lyon
  • James R Lupski

Abstract

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.

Bibliografische Daten

OriginalspracheEnglisch
ISSN0002-9297
DOIs
StatusVeröffentlicht - 01.08.2019

Anmerkungen des Dekanats

Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PubMed 31256877