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.
| Language | English |
|---|---|
| Article number | 1916 |
| Pages | 343-352 |
| Number of pages | 10 |
| Journal | American Journal of Human Genetics |
| Volume | 97 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 6 Aug 2015 |
| Externally published | Yes |
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
}
Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. / Snijders Blok, Lot; Madsen, Erik; Juusola, Jane; Gilissen, Christian; Baralle, Diana; Reijnders, Margot R.F.; Venselaar, Hanka; Helsmoortel, Céline; Cho, Megan T.; Hoischen, Alexander; Vissers, Lisenka E.L.M.; Koemans, Tom S.; Wissink-Lindhout, Willemijn; Eichler, Evan E.; Romano, Corrado; Van Esch, Hilde; Stumpel, Connie; Vreeburg, Maaike; Smeets, Eric; Oberndorff, Karin; Van Bon, Bregje W.M.; Shaw, Marie; Gecz, Jozef; Haan, Eric; Bienek, Melanie; Jensen, Corinna; Loeys, Bart L.; Van Dijck, Anke; Innes, A. Micheil; Racher, Hilary; Vermeer, Sascha; Di Donato, Nataliya; Rump, Andreas; Tatton-Brown, Katrina; Parker, Michael J.; Henderson, Alex; Lynch, Sally A.; Fryer, Alan; Ross, Alison; Vasudevan, Pradeep; Kini, Usha; Newbury-Ecob, Ruth; Chandler, Kate; Male, Alison; Dijkstra, Sybe; Schieving, Jolanda; Giltay, Jacques; Van gassen, Koen L.I.; Schuurs-Hoeijmakers, Janneke; Tan, Perciliz L.; Pediaditakis, Igor; Haas, Stefan A.; Retterer, Kyle; Reed, Patrick; Monaghan, Kristin G.; Haverfield, Eden; Natowicz, Marvin; Myers, Angela; Kruer, Michael C.; Stein, Quinn; Strauss, Kevin A.; Brigatti, Karlla W.; Keating, Katherine; Burton, Barbara K.; Kim, Katherine H.; Charrow, Joel; Norman, Jennifer; Foster-Barber, Audrey; Kline, Antonie D.; Kimball, Amy; Zackai, Elaine; Harr, Margaret; Fox, Joyce; McLaughlin, Julie; Lindstrom, Kristin; Haude, Katrina M.; Van Roozendaal, Kees; Brunner, Han; Chung, Wendy K.; Kooy, R. Frank; Pfundt, Rolph; Kalscheuer, Vera; Mehta, Sarju G.; Katsanis, Nicholas; Kleefstra, Tjitske.
In: American Journal of Human Genetics, Vol. 97, No. 2, 1916, 06.08.2015, p. 343-352.Research output: Contribution to journal › Article
TY - JOUR
T1 - Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling
AU - Snijders Blok, Lot
AU - Madsen, Erik
AU - Juusola, Jane
AU - Gilissen, Christian
AU - Baralle, Diana
AU - Reijnders, Margot R.F.
AU - Venselaar, Hanka
AU - Helsmoortel, Céline
AU - Cho, Megan T.
AU - Hoischen, Alexander
AU - Vissers, Lisenka E.L.M.
AU - Koemans, Tom S.
AU - Wissink-Lindhout, Willemijn
AU - Eichler, Evan E.
AU - Romano, Corrado
AU - Van Esch, Hilde
AU - Stumpel, Connie
AU - Vreeburg, Maaike
AU - Smeets, Eric
AU - Oberndorff, Karin
AU - Van Bon, Bregje W.M.
AU - Shaw, Marie
AU - Gecz, Jozef
AU - Haan, Eric
AU - Bienek, Melanie
AU - Jensen, Corinna
AU - Loeys, Bart L.
AU - Van Dijck, Anke
AU - Innes, A. Micheil
AU - Racher, Hilary
AU - Vermeer, Sascha
AU - Di Donato, Nataliya
AU - Rump, Andreas
AU - Tatton-Brown, Katrina
AU - Parker, Michael J.
AU - Henderson, Alex
AU - Lynch, Sally A.
AU - Fryer, Alan
AU - Ross, Alison
AU - Vasudevan, Pradeep
AU - Kini, Usha
AU - Newbury-Ecob, Ruth
AU - Chandler, Kate
AU - Male, Alison
AU - Dijkstra, Sybe
AU - Schieving, Jolanda
AU - Giltay, Jacques
AU - Van gassen, Koen L.I.
AU - Schuurs-Hoeijmakers, Janneke
AU - Tan, Perciliz L.
AU - Pediaditakis, Igor
AU - Haas, Stefan A.
AU - Retterer, Kyle
AU - Reed, Patrick
AU - Monaghan, Kristin G.
AU - Haverfield, Eden
AU - Natowicz, Marvin
AU - Myers, Angela
AU - Kruer, Michael C.
AU - Stein, Quinn
AU - Strauss, Kevin A.
AU - Brigatti, Karlla W.
AU - Keating, Katherine
AU - Burton, Barbara K.
AU - Kim, Katherine H.
AU - Charrow, Joel
AU - Norman, Jennifer
AU - Foster-Barber, Audrey
AU - Kline, Antonie D.
AU - Kimball, Amy
AU - Zackai, Elaine
AU - Harr, Margaret
AU - Fox, Joyce
AU - McLaughlin, Julie
AU - Lindstrom, Kristin
AU - Haude, Katrina M.
AU - Van Roozendaal, Kees
AU - Brunner, Han
AU - Chung, Wendy K.
AU - Kooy, R. Frank
AU - Pfundt, Rolph
AU - Kalscheuer, Vera
AU - Mehta, Sarju G.
AU - Katsanis, Nicholas
AU - Kleefstra, Tjitske
PY - 2015/8/6
Y1 - 2015/8/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84938978665&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2015.07.004
DO - 10.1016/j.ajhg.2015.07.004
M3 - Article
VL - 97
SP - 343
EP - 352
JO - American Journal of Human Genetics
T2 - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
M1 - 1916
ER -