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Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling
Authors
Diana Baralle
Melanie Bienek
+83 more
Lot Snijders Blok
Karlla W Brigatti
Han Brunner
Barbara K Burton
Kate Chandler
Joel Charrow
Megan T Cho
Wendy K Chung
Nataliya Di Donato
Sybe Dijkstra
Evan E Eichler
Audrey Foster-Barber
Joyce Fox
Alan Fryer
Jozef Gecz
Christian Gilissen
Jacques Giltay
Eric Haan
Stefan A Haas
Margaret Harr
Katrina M Haude
Eden Haverfield
Celine Helsmoorte
Alex Henderson
Alexander Hoischen
A Micheil Innes
Corinna Jensen
Jane Juusola
Vera Kalscheuer
Nicholas Katsanis
Katherine Keating
Katherine H Kim
Amy Kimball
Usha Kini
Tjitske Kleefstra
Antonie D Kline
Tom S Koemans
R Frank Kooy
Michael C Kruer
Kristin Lindstrom
Bart L Loeys
Sally A Lynch
Erik Madsen
Alison Male
Julie McLaughlin
Sarju G Mehta
Kristin G Monaghan
Angela Myers
Marvin Natowicz
Ruth Newbury-Ecob
Jennifer Norman
Karin Obemdorff
Michael J Parker
Igor Pediaditakis
Rolph Pfundt
Hilary Racher
Patrick Reed
Margot RF Reijnders
Kyle Retterer
Corrado Romano
Alison Ross
Andreas Rump
Jolanda Schieving
Janneke Schuurs-Hoeijmakers
Marie Shaw
Eric Smeets
Quinn Stein
Kevin A Strauss
Connie Stumpel
Perciliz L Tan
Katrina Tatton-Brown
Bregje WM van Bon
Anke Van Diick
Hilde Van Esch
Koen LI Van Gassen
Kees van Roozendaal
Pradeep Vasudevan
Hanka Venselaar
Sascha Vermeer
Lisenka ELM Vissers
Maaike Vreeburg
Willemijn Wissink-Lindhout
Elaine Zackai
Publication date
6 August 2015
Publisher
'Elsevier BV'
Doi
Cite
Abstract
Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.publisher: Elsevier articletitle: Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling journaltitle: The American Journal of Human Genetics articlelink: http://dx.doi.org/10.1016/j.ajhg.2015.07.004 content_type: article copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.status: publishe
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