Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes

Claudia M.B. Carvalho; Shivakumar Vasanth; Marwan Shinawi; Chad Russell; Melissa B. Ramocki; Chester W. Brown; Jesper Graakjaer; Anne Bine Skytte; Angela M. Vianna-Morgante; Ana C.V. Krepischi; Gayle S. Patel; La Donna Immken; Kyrieckos Aleck; Cynthia Lim; Sau Wai Cheung; Carla Rosenberg; Elias Nicholas Katsanis; James R. Lupski

doi:10.1016/j.ajhg.2014.10.006

Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes

Claudia M.B. Carvalho, Shivakumar Vasanth, Marwan Shinawi, Chad Russell, Melissa B. Ramocki, Chester W. Brown, Jesper Graakjaer, Anne Bine Skytte, Angela M. Vianna-Morgante, Ana C.V. Krepischi, Gayle S. Patel, La Donna Immken, Kyrieckos Aleck, Cynthia Lim, Sau Wai Cheung, Carla Rosenberg, Elias Nicholas Katsanis^*, James R. Lupski

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly.We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.

Original language	English (US)
Pages (from-to)	565-578
Number of pages	14
Journal	American journal of human genetics
Volume	95
Issue number	5
DOIs	https://doi.org/10.1016/j.ajhg.2014.10.006
State	Published - 2014

Funding

We thank the families for their participation in the study. This work was supported in part by US National Institute of Neurological Disorders and Stroke (NINDS) grants R01 NS058529 to J.R.L. and 5K08NS062711 to M.B.R.; US National Human Genome Research Institute/National Heart Blood and Lung Institute (NHGRI/NHBLI) grant U54HG006542 to J.R.L.; by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), a Young Investigator fellowship from the Science without Borders Program grant 402520/2012-2 to C.M.B.C.; and a grant from the Simons Foundation to N.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS, NHGRI, NIH, or CNPq. J.R.L. holds stock ownership in 23andMe, Inc., and is a coinventor on multiple United States and European patents related to molecular diagnostics. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered in the Medical Genetics Laboratories.

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Carvalho, C. M. B., Vasanth, S., Shinawi, M., Russell, C., Ramocki, M. B., Brown, C. W., Graakjaer, J., Skytte, A. B., Vianna-Morgante, A. M., Krepischi, A. C. V., Patel, G. S., Immken, L. D., Aleck, K., Lim, C., Cheung, S. W., Rosenberg, C., Katsanis, E. N., & Lupski, J. R. (2014). Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes. American journal of human genetics, 95(5), 565-578. https://doi.org/10.1016/j.ajhg.2014.10.006

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title = "Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes",

abstract = "The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly.We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.",

author = "Carvalho, {Claudia M.B.} and Shivakumar Vasanth and Marwan Shinawi and Chad Russell and Ramocki, {Melissa B.} and Brown, {Chester W.} and Jesper Graakjaer and Skytte, {Anne Bine} and Vianna-Morgante, {Angela M.} and Krepischi, {Ana C.V.} and Patel, {Gayle S.} and Immken, {La Donna} and Kyrieckos Aleck and Cynthia Lim and Cheung, {Sau Wai} and Carla Rosenberg and Katsanis, {Elias Nicholas} and Lupski, {James R.}",

year = "2014",

doi = "10.1016/j.ajhg.2014.10.006",

language = "English (US)",

volume = "95",

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Carvalho, CMB, Vasanth, S, Shinawi, M, Russell, C, Ramocki, MB, Brown, CW, Graakjaer, J, Skytte, AB, Vianna-Morgante, AM, Krepischi, ACV, Patel, GS, Immken, LD, Aleck, K, Lim, C, Cheung, SW, Rosenberg, C, Katsanis, EN & Lupski, JR 2014, 'Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes', American journal of human genetics, vol. 95, no. 5, pp. 565-578. https://doi.org/10.1016/j.ajhg.2014.10.006

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AU - Carvalho, Claudia M.B.

AU - Vasanth, Shivakumar

AU - Shinawi, Marwan

AU - Russell, Chad

AU - Ramocki, Melissa B.

AU - Brown, Chester W.

AU - Graakjaer, Jesper

AU - Skytte, Anne Bine

AU - Vianna-Morgante, Angela M.

AU - Krepischi, Ana C.V.

AU - Patel, Gayle S.

AU - Immken, La Donna

AU - Aleck, Kyrieckos

AU - Lim, Cynthia

AU - Cheung, Sau Wai

AU - Rosenberg, Carla

AU - Katsanis, Elias Nicholas

AU - Lupski, James R.

PY - 2014

Y1 - 2014

N2 - The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly.We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.

AB - The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly.We identified five subjects with copy-number variants (CNVs) on 17p13.1 for whom we performed detailed clinical and molecular studies. Breakpoint mapping and retrospective analysis of published cases refined the smallest region of overlap (SRO) for microcephaly to a genomic interval containing nine genes. Dissection of this phenotype in zebrafish embryos revealed a complex genetic architecture: dosage perturbation of four genes (ASGR1, ACADVL, DVL2, and GABARAP) impeded neurodevelopment and decreased dosage of the same loci caused a reduced mitotic index in vitro. Moreover, epistatic analyses in vivo showed that dosage perturbations of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO.

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Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes

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