Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing

Janneke H M Schuurs-Hoeijmakers, Anneke T. Vulto-Van Silfhout, Lisenka E L M Vissers, Ilse I G M Van De Vondervoort, Bregje W M Van Bon, Joep De Ligt, Christian Gilissen, Jayne Y. Hehir-Kwa, Kornelia Neveling, Marisol Del Rosario, Gausiya Hira, Santina Reitano, Aurelio Vitello, Pinella Failla, Donatella Greco, Marco Fichera, Ornella Galesi, Tjitske Kleefstra, Marie T. Greally, Charlotte W. OckeloenMarjolein H. Willemsen, Ernie M H F Bongers, Irene M. Janssen, Rolph Pfundt, Joris A. Veltman, Corrado Romano, Michèl A. Willemsen, Hans Van Bokhoven, Han G. Brunner, Bert B A De Vries, Arjan P M De Brouwer

Research output: Contribution to journalArticle

Abstract

Background: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. Objectives: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Nonconsanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. Methods and results: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. Conclusions: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.

Original languageEnglish
Pages (from-to)802-811
Number of pages10
JournalJournal of Medical Genetics
Volume50
Issue number12
DOIs
Publication statusPublished - 2013

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Exome
Siblings
Intellectual Disability
Genes
Mutation
X Chromosome
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Schuurs-Hoeijmakers, J. H. M., Vulto-Van Silfhout, A. T., Vissers, L. E. L. M., Van De Vondervoort, I. I. G. M., Van Bon, B. W. M., De Ligt, J., ... De Brouwer, A. P. M. (2013). Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. Journal of Medical Genetics, 50(12), 802-811. https://doi.org/10.1136/jmedgenet-2013-101644

Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. / Schuurs-Hoeijmakers, Janneke H M; Vulto-Van Silfhout, Anneke T.; Vissers, Lisenka E L M; Van De Vondervoort, Ilse I G M; Van Bon, Bregje W M; De Ligt, Joep; Gilissen, Christian; Hehir-Kwa, Jayne Y.; Neveling, Kornelia; Del Rosario, Marisol; Hira, Gausiya; Reitano, Santina; Vitello, Aurelio; Failla, Pinella; Greco, Donatella; Fichera, Marco; Galesi, Ornella; Kleefstra, Tjitske; Greally, Marie T.; Ockeloen, Charlotte W.; Willemsen, Marjolein H.; Bongers, Ernie M H F; Janssen, Irene M.; Pfundt, Rolph; Veltman, Joris A.; Romano, Corrado; Willemsen, Michèl A.; Van Bokhoven, Hans; Brunner, Han G.; De Vries, Bert B A; De Brouwer, Arjan P M.

In: Journal of Medical Genetics, Vol. 50, No. 12, 2013, p. 802-811.

Research output: Contribution to journalArticle

Schuurs-Hoeijmakers, JHM, Vulto-Van Silfhout, AT, Vissers, LELM, Van De Vondervoort, IIGM, Van Bon, BWM, De Ligt, J, Gilissen, C, Hehir-Kwa, JY, Neveling, K, Del Rosario, M, Hira, G, Reitano, S, Vitello, A, Failla, P, Greco, D, Fichera, M, Galesi, O, Kleefstra, T, Greally, MT, Ockeloen, CW, Willemsen, MH, Bongers, EMHF, Janssen, IM, Pfundt, R, Veltman, JA, Romano, C, Willemsen, MA, Van Bokhoven, H, Brunner, HG, De Vries, BBA & De Brouwer, APM 2013, 'Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing', Journal of Medical Genetics, vol. 50, no. 12, pp. 802-811. https://doi.org/10.1136/jmedgenet-2013-101644
Schuurs-Hoeijmakers JHM, Vulto-Van Silfhout AT, Vissers LELM, Van De Vondervoort IIGM, Van Bon BWM, De Ligt J et al. Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. Journal of Medical Genetics. 2013;50(12):802-811. https://doi.org/10.1136/jmedgenet-2013-101644
Schuurs-Hoeijmakers, Janneke H M ; Vulto-Van Silfhout, Anneke T. ; Vissers, Lisenka E L M ; Van De Vondervoort, Ilse I G M ; Van Bon, Bregje W M ; De Ligt, Joep ; Gilissen, Christian ; Hehir-Kwa, Jayne Y. ; Neveling, Kornelia ; Del Rosario, Marisol ; Hira, Gausiya ; Reitano, Santina ; Vitello, Aurelio ; Failla, Pinella ; Greco, Donatella ; Fichera, Marco ; Galesi, Ornella ; Kleefstra, Tjitske ; Greally, Marie T. ; Ockeloen, Charlotte W. ; Willemsen, Marjolein H. ; Bongers, Ernie M H F ; Janssen, Irene M. ; Pfundt, Rolph ; Veltman, Joris A. ; Romano, Corrado ; Willemsen, Michèl A. ; Van Bokhoven, Hans ; Brunner, Han G. ; De Vries, Bert B A ; De Brouwer, Arjan P M. / Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing. In: Journal of Medical Genetics. 2013 ; Vol. 50, No. 12. pp. 802-811.
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abstract = "Background: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3{\%} of the general population. Mutations in more than 10{\%} of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. Objectives: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Nonconsanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. Methods and results: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. Conclusions: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.",
author = "Schuurs-Hoeijmakers, {Janneke H M} and {Vulto-Van Silfhout}, {Anneke T.} and Vissers, {Lisenka E L M} and {Van De Vondervoort}, {Ilse I G M} and {Van Bon}, {Bregje W M} and {De Ligt}, Joep and Christian Gilissen and Hehir-Kwa, {Jayne Y.} and Kornelia Neveling and {Del Rosario}, Marisol and Gausiya Hira and Santina Reitano and Aurelio Vitello and Pinella Failla and Donatella Greco and Marco Fichera and Ornella Galesi and Tjitske Kleefstra and Greally, {Marie T.} and Ockeloen, {Charlotte W.} and Willemsen, {Marjolein H.} and Bongers, {Ernie M H F} and Janssen, {Irene M.} and Rolph Pfundt and Veltman, {Joris A.} and Corrado Romano and Willemsen, {Mich{\`e}l A.} and {Van Bokhoven}, Hans and Brunner, {Han G.} and {De Vries}, {Bert B A} and {De Brouwer}, {Arjan P M}",
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T1 - Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing

AU - Schuurs-Hoeijmakers, Janneke H M

AU - Vulto-Van Silfhout, Anneke T.

AU - Vissers, Lisenka E L M

AU - Van De Vondervoort, Ilse I G M

AU - Van Bon, Bregje W M

AU - De Ligt, Joep

AU - Gilissen, Christian

AU - Hehir-Kwa, Jayne Y.

AU - Neveling, Kornelia

AU - Del Rosario, Marisol

AU - Hira, Gausiya

AU - Reitano, Santina

AU - Vitello, Aurelio

AU - Failla, Pinella

AU - Greco, Donatella

AU - Fichera, Marco

AU - Galesi, Ornella

AU - Kleefstra, Tjitske

AU - Greally, Marie T.

AU - Ockeloen, Charlotte W.

AU - Willemsen, Marjolein H.

AU - Bongers, Ernie M H F

AU - Janssen, Irene M.

AU - Pfundt, Rolph

AU - Veltman, Joris A.

AU - Romano, Corrado

AU - Willemsen, Michèl A.

AU - Van Bokhoven, Hans

AU - Brunner, Han G.

AU - De Vries, Bert B A

AU - De Brouwer, Arjan P M

PY - 2013

Y1 - 2013

N2 - Background: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. Objectives: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Nonconsanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. Methods and results: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. Conclusions: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.

AB - Background: Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. Objectives: We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Nonconsanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. Methods and results: Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. Conclusions: We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.

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