Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Lot Snijders Blok, Erik Madsen, Jane Juusola, Christian Gilissen, Diana Baralle, Margot R F Reijnders, Hanka Venselaar, Céline Helsmoortel, Megan T. Cho, Alexander Hoischen, Lisenka E L M Vissers, Tom S. Koemans, Willemijn Wissink-Lindhout, Evan E. Eichler, Corrado Romano, Hilde Van Esch, Connie Stumpel, Maaike Vreeburg, Eric Smeets, Karin OberndorffBregje W M Van Bon, Marie Shaw, Jozef Gecz, Eric Haan, Melanie Bienek, Corinna Jensen, Bart L. Loeys, Anke Van Dijck, A. Micheil Innes, Hilary Racher, Sascha Vermeer, Nataliya Di Donato, Andreas Rump, Katrina Tatton-Brown, Michael J. Parker, Alex Henderson, Sally A. Lynch, Alan Fryer, Alison Ross, Pradeep Vasudevan, Usha Kini, Ruth Newbury-Ecob, Kate Chandler, Alison Male, Sybe Dijkstra, Jolanda Schieving, Jacques Giltay, Koen L I Van gassen, Janneke Schuurs-Hoeijmakers, Perciliz L. Tan, Igor Pediaditakis, Stefan A. Haas, Kyle Retterer, Patrick Reed, Kristin G. Monaghan, Eden Haverfield, Marvin Natowicz, Angela Myers, Michael C. Kruer, Quinn Stein, Kevin A. Strauss, Karlla W. Brigatti, Katherine Keating, Barbara K. Burton, Katherine H. Kim, Joel Charrow, Jennifer Norman, Audrey Foster-Barber, Antonie D. Kline, Amy Kimball, Elaine Zackai, Margaret Harr, Joyce Fox, Julie McLaughlin, Kristin Lindstrom, Katrina M. Haude, Kees Van Roozendaal, Han Brunner, Wendy K. Chung, R. Frank Kooy, Rolph Pfundt, Vera Kalscheuer, Sarju G. Mehta, Nicholas Katsanis, Tjitske Kleefstra

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish
Article number1916
Pages (from-to)343-352
Number of pages10
JournalAmerican Journal of Human Genetics
Volume97
Issue number2
DOIs
Publication statusPublished - Aug 6 2015

Fingerprint

Intellectual Disability
Mutation
X-Linked Genes
Exome
Sexism
Inheritance Patterns
Wnt Signaling Pathway
Muscle Hypotonia
Corpus Callosum
Movement Disorders
X Chromosome
Zebrafish
Missense Mutation
Epilepsy
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Snijders Blok, L., Madsen, E., Juusola, J., Gilissen, C., Baralle, D., Reijnders, M. R. F., ... Kleefstra, T. (2015). Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. American Journal of Human Genetics, 97(2), 343-352. [1916]. https://doi.org/10.1016/j.ajhg.2015.07.004

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 journalArticle

Snijders Blok, L, Madsen, E, Juusola, J, Gilissen, C, Baralle, D, Reijnders, MRF, Venselaar, H, Helsmoortel, C, Cho, MT, Hoischen, A, Vissers, LELM, Koemans, TS, Wissink-Lindhout, W, Eichler, EE, Romano, C, Van Esch, H, Stumpel, C, Vreeburg, M, Smeets, E, Oberndorff, K, Van Bon, BWM, Shaw, M, Gecz, J, Haan, E, Bienek, M, Jensen, C, Loeys, BL, Van Dijck, A, Innes, AM, Racher, H, Vermeer, S, Di Donato, N, Rump, A, Tatton-Brown, K, Parker, MJ, Henderson, A, Lynch, SA, Fryer, A, Ross, A, Vasudevan, P, Kini, U, Newbury-Ecob, R, Chandler, K, Male, A, Dijkstra, S, Schieving, J, Giltay, J, Van gassen, KLI, Schuurs-Hoeijmakers, J, Tan, PL, Pediaditakis, I, Haas, SA, Retterer, K, Reed, P, Monaghan, KG, Haverfield, E, Natowicz, M, Myers, A, Kruer, MC, Stein, Q, Strauss, KA, Brigatti, KW, Keating, K, Burton, BK, Kim, KH, Charrow, J, Norman, J, Foster-Barber, A, Kline, AD, Kimball, A, Zackai, E, Harr, M, Fox, J, McLaughlin, J, Lindstrom, K, Haude, KM, Van Roozendaal, K, Brunner, H, Chung, WK, Kooy, RF, Pfundt, R, Kalscheuer, V, Mehta, SG, Katsanis, N & Kleefstra, T 2015, 'Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling', American Journal of Human Genetics, vol. 97, no. 2, 1916, pp. 343-352. https://doi.org/10.1016/j.ajhg.2015.07.004
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. / Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling. In: American Journal of Human Genetics. 2015 ; Vol. 97, No. 2. pp. 343-352.
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title = "Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling",
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.",
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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.

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