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De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo los... Full description

Journal Title: American journal of human genetics 2016, Vol.98 (2), p.373-381
Main Author: Reijnders, Margot R.F
Other Authors: Zachariadis, Vasilios , Latour, Brooke , Jolly, Lachlan , Mancini, Grazia M , Pfundt, Rolph , Wu, Ka Man , van Ravenswaaij-Arts, Conny M.A , Veenstra-Knol, Hermine E , Anderlid, Britt-Marie M , Wood, Stephen A , Cheung, Sau Wai , Barnicoat, Angela , Probst, Frank , Magoulas, Pilar , Brooks, Alice S , Malmgren, Helena , Harila-Saari, Arja , Marcelis, Carlo M , Vreeburg, Maaike , Hobson, Emma , Sutton, V. Reid , Stark, Zornitza , Vogt, Julie , Cooper, Nicola , Lim, Jiin Ying , Price, Sue , Lai, Angeline Hwei Meeng , Domingo, Deepti , Reversade, Bruno , Gecz, Jozef , Gilissen, Christian , Brunner, Han G , Kini, Usha , Roepman, Ronald , Nordgren, Ann , Kleefstra, Tjitske
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0002-9297
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title: De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations
format: Article
creator:
  • Reijnders, Margot R.F
  • Zachariadis, Vasilios
  • Latour, Brooke
  • Jolly, Lachlan
  • Mancini, Grazia M
  • Pfundt, Rolph
  • Wu, Ka Man
  • van Ravenswaaij-Arts, Conny M.A
  • Veenstra-Knol, Hermine E
  • Anderlid, Britt-Marie M
  • Wood, Stephen A
  • Cheung, Sau Wai
  • Barnicoat, Angela
  • Probst, Frank
  • Magoulas, Pilar
  • Brooks, Alice S
  • Malmgren, Helena
  • Harila-Saari, Arja
  • Marcelis, Carlo M
  • Vreeburg, Maaike
  • Hobson, Emma
  • Sutton, V. Reid
  • Stark, Zornitza
  • Vogt, Julie
  • Cooper, Nicola
  • Lim, Jiin Ying
  • Price, Sue
  • Lai, Angeline Hwei Meeng
  • Domingo, Deepti
  • Reversade, Bruno
  • Gecz, Jozef
  • Gilissen, Christian
  • Brunner, Han G
  • Kini, Usha
  • Roepman, Ronald
  • Nordgren, Ann
  • Kleefstra, Tjitske
subjects:
  • Adolescent
  • Base Sequence
  • Child
  • Child development deviations
  • Child, Preschool
  • Choanal Atresia - diagnosis
  • Choanal Atresia - genetics
  • Congenital diseases
  • Developmental disabilities
  • Developmental Disabilities - diagnosis
  • Developmental Disabilities - genetics
  • Female
  • Females
  • Gene mutations
  • Genes
  • Genes, X-Linked
  • Genetic aspects
  • Genetic disorders
  • Genetic Testing
  • Genetics
  • Genetics(clinical)
  • Humans
  • Intellectual Disability - diagnosis
  • Intellectual Disability - genetics
  • Medicin och hälsovetenskap
  • Molecular Sequence Data
  • Mutation
  • Observations
  • Phenotype
  • Physiological aspects
  • Report
  • Ubiquitin Thiolesterase - genetics
  • Ubiquitin Thiolesterase - metabolism
  • X Chromosome Inactivation
  • Young Adult
ispartof: American journal of human genetics, 2016, Vol.98 (2), p.373-381
description: Mutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
  • 1537-6605
url: Link


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titleDe Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations
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creatorReijnders, Margot R.F ; Zachariadis, Vasilios ; Latour, Brooke ; Jolly, Lachlan ; Mancini, Grazia M ; Pfundt, Rolph ; Wu, Ka Man ; van Ravenswaaij-Arts, Conny M.A ; Veenstra-Knol, Hermine E ; Anderlid, Britt-Marie M ; Wood, Stephen A ; Cheung, Sau Wai ; Barnicoat, Angela ; Probst, Frank ; Magoulas, Pilar ; Brooks, Alice S ; Malmgren, Helena ; Harila-Saari, Arja ; Marcelis, Carlo M ; Vreeburg, Maaike ; Hobson, Emma ; Sutton, V. Reid ; Stark, Zornitza ; Vogt, Julie ; Cooper, Nicola ; Lim, Jiin Ying ; Price, Sue ; Lai, Angeline Hwei Meeng ; Domingo, Deepti ; Reversade, Bruno ; Gecz, Jozef ; Gilissen, Christian ; Brunner, Han G ; Kini, Usha ; Roepman, Ronald ; Nordgren, Ann ; Kleefstra, Tjitske
creatorcontribReijnders, Margot R.F ; Zachariadis, Vasilios ; Latour, Brooke ; Jolly, Lachlan ; Mancini, Grazia M ; Pfundt, Rolph ; Wu, Ka Man ; van Ravenswaaij-Arts, Conny M.A ; Veenstra-Knol, Hermine E ; Anderlid, Britt-Marie M ; Wood, Stephen A ; Cheung, Sau Wai ; Barnicoat, Angela ; Probst, Frank ; Magoulas, Pilar ; Brooks, Alice S ; Malmgren, Helena ; Harila-Saari, Arja ; Marcelis, Carlo M ; Vreeburg, Maaike ; Hobson, Emma ; Sutton, V. Reid ; Stark, Zornitza ; Vogt, Julie ; Cooper, Nicola ; Lim, Jiin Ying ; Price, Sue ; Lai, Angeline Hwei Meeng ; Domingo, Deepti ; Reversade, Bruno ; Gecz, Jozef ; Gilissen, Christian ; Brunner, Han G ; Kini, Usha ; Roepman, Ronald ; Nordgren, Ann ; Kleefstra, Tjitske ; the DDD Study ; DDD Study
descriptionMutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.
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1ISSN: 1537-6605
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languageeng
publisherUnited States: Elsevier Inc
subjectAdolescent ; Base Sequence ; Child ; Child development deviations ; Child, Preschool ; Choanal Atresia - diagnosis ; Choanal Atresia - genetics ; Congenital diseases ; Developmental disabilities ; Developmental Disabilities - diagnosis ; Developmental Disabilities - genetics ; Female ; Females ; Gene mutations ; Genes ; Genes, X-Linked ; Genetic aspects ; Genetic disorders ; Genetic Testing ; Genetics ; Genetics(clinical) ; Humans ; Intellectual Disability - diagnosis ; Intellectual Disability - genetics ; Medicin och hälsovetenskap ; Molecular Sequence Data ; Mutation ; Observations ; Phenotype ; Physiological aspects ; Report ; Ubiquitin Thiolesterase - genetics ; Ubiquitin Thiolesterase - metabolism ; X Chromosome Inactivation ; Young Adult
ispartofAmerican journal of human genetics, 2016, Vol.98 (2), p.373-381
rights
02016 The American Society of Human Genetics
1info:eu-repo/semantics/restrictedAccess
2Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
3COPYRIGHT 2016 Elsevier B.V.
4Copyright Cell Press Feb 4, 2016
52016 by The American Society of Human Genetics. All rights reserved. 2016 The American Society of Human Genetics
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0Reijnders, Margot R.F
1Zachariadis, Vasilios
2Latour, Brooke
3Jolly, Lachlan
4Mancini, Grazia M
5Pfundt, Rolph
6Wu, Ka Man
7van Ravenswaaij-Arts, Conny M.A
8Veenstra-Knol, Hermine E
9Anderlid, Britt-Marie M
10Wood, Stephen A
11Cheung, Sau Wai
12Barnicoat, Angela
13Probst, Frank
14Magoulas, Pilar
15Brooks, Alice S
16Malmgren, Helena
17Harila-Saari, Arja
18Marcelis, Carlo M
19Vreeburg, Maaike
20Hobson, Emma
21Sutton, V. Reid
22Stark, Zornitza
23Vogt, Julie
24Cooper, Nicola
25Lim, Jiin Ying
26Price, Sue
27Lai, Angeline Hwei Meeng
28Domingo, Deepti
29Reversade, Bruno
30Gecz, Jozef
31Gilissen, Christian
32Brunner, Han G
33Kini, Usha
34Roepman, Ronald
35Nordgren, Ann
36Kleefstra, Tjitske
37the DDD Study
38DDD Study
title
0De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations
1American journal of human genetics
addtitleAm J Hum Genet
descriptionMutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.
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11Female
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13Gene mutations
14Genes
15Genes, X-Linked
16Genetic aspects
17Genetic disorders
18Genetic Testing
19Genetics
20Genetics(clinical)
21Humans
22Intellectual Disability - diagnosis
23Intellectual Disability - genetics
24Medicin och hälsovetenskap
25Molecular Sequence Data
26Mutation
27Observations
28Phenotype
29Physiological aspects
30Report
31Ubiquitin Thiolesterase - genetics
32Ubiquitin Thiolesterase - metabolism
33X Chromosome Inactivation
34Young Adult
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7van Ravenswaaij-Arts, Conny M.A
8Veenstra-Knol, Hermine E
9Anderlid, Britt-Marie M
10Wood, Stephen A
11Cheung, Sau Wai
12Barnicoat, Angela
13Probst, Frank
14Magoulas, Pilar
15Brooks, Alice S
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17Harila-Saari, Arja
18Marcelis, Carlo M
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31Gilissen, Christian
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titleDe Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations
authorReijnders, Margot R.F ; Zachariadis, Vasilios ; Latour, Brooke ; Jolly, Lachlan ; Mancini, Grazia M ; Pfundt, Rolph ; Wu, Ka Man ; van Ravenswaaij-Arts, Conny M.A ; Veenstra-Knol, Hermine E ; Anderlid, Britt-Marie M ; Wood, Stephen A ; Cheung, Sau Wai ; Barnicoat, Angela ; Probst, Frank ; Magoulas, Pilar ; Brooks, Alice S ; Malmgren, Helena ; Harila-Saari, Arja ; Marcelis, Carlo M ; Vreeburg, Maaike ; Hobson, Emma ; Sutton, V. Reid ; Stark, Zornitza ; Vogt, Julie ; Cooper, Nicola ; Lim, Jiin Ying ; Price, Sue ; Lai, Angeline Hwei Meeng ; Domingo, Deepti ; Reversade, Bruno ; Gecz, Jozef ; Gilissen, Christian ; Brunner, Han G ; Kini, Usha ; Roepman, Ronald ; Nordgren, Ann ; Kleefstra, Tjitske
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32Ubiquitin Thiolesterase - metabolism
33X Chromosome Inactivation
34Young Adult
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31Gilissen, Christian
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pages373-381
issn
00002-9297
11537-6605
eissn1537-6605
notesThese authors contributed equally
abstractMutations in more than a hundred genes have been reported to cause X-linked recessive intellectual disability (ID) mainly in males. In contrast, the number of identified X-linked genes in which de novo mutations specifically cause ID in females is limited. Here, we report 17 females with de novo loss-of-function mutations in USP9X, encoding a highly conserved deubiquitinating enzyme. The females in our study have a specific phenotype that includes ID/developmental delay (DD), characteristic facial features, short stature, and distinct congenital malformations comprising choanal atresia, anal abnormalities, post-axial polydactyly, heart defects, hypomastia, cleft palate/bifid uvula, progressive scoliosis, and structural brain abnormalities. Four females from our cohort were identified by targeted genetic testing because their phenotype was suggestive for USP9X mutations. In several females, pigment changes along Blaschko lines and body asymmetry were observed, which is probably related to differential (escape from) X-inactivation between tissues. Expression studies on both mRNA and protein level in affected-female-derived fibroblasts showed significant reduction of USP9X level, confirming the loss-of-function effect of the identified mutations. Given that some features of affected females are also reported in known ciliopathy syndromes, we examined the role of USP9X in the primary cilium and found that endogenous USP9X localizes along the length of the ciliary axoneme, indicating that its loss of function could indeed disrupt cilium-regulated processes. Absence of dysregulated ciliary parameters in affected female-derived fibroblasts, however, points toward spatiotemporal specificity of ciliary USP9X (dys-)function.
copUnited States
pubElsevier Inc
pmid26833328
doi10.1016/j.ajhg.2015.12.015
oafree_for_read