Whole-exome sequencing for variant discovery in blepharospasm

Jun Tian, Satya R. Vemula, Jianfeng Xiao, Enza Maria Valente, Giovanni Defazio, Simona Petrucci, Angelo Fabio Gigante, Monika Rudzińska-Bar, Zbigniew K Wszolek, Kathleen Kennelly, Ryan J. Uitti, Jay A Van Gerpen, Peter Hedera, Elizabeth J. Trimble, Mark S. Ledoux

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation. Methods: We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis. Results: Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia. Conclusions: Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.

Original languageEnglish (US)
JournalMolecular Genetics and Genomic Medicine
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Blepharospasm
Exome
Pedigree
Penetrance
Dystonia
Multifactorial Inheritance
Dystonic Disorders
Torticollis
Inheritance Patterns
Spasm
Ataxia
Migraine Disorders
Nuclear Family
Age of Onset
Fathers
Computer Simulation
Mutation

Keywords

  • Blepharospasm
  • Cerebellum
  • Dystonia
  • Purkinje cell
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Tian, J., Vemula, S. R., Xiao, J., Valente, E. M., Defazio, G., Petrucci, S., ... Ledoux, M. S. (Accepted/In press). Whole-exome sequencing for variant discovery in blepharospasm. Molecular Genetics and Genomic Medicine. https://doi.org/10.1002/mgg3.411

Whole-exome sequencing for variant discovery in blepharospasm. / Tian, Jun; Vemula, Satya R.; Xiao, Jianfeng; Valente, Enza Maria; Defazio, Giovanni; Petrucci, Simona; Gigante, Angelo Fabio; Rudzińska-Bar, Monika; Wszolek, Zbigniew K; Kennelly, Kathleen; Uitti, Ryan J.; Van Gerpen, Jay A; Hedera, Peter; Trimble, Elizabeth J.; Ledoux, Mark S.

In: Molecular Genetics and Genomic Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Tian, J, Vemula, SR, Xiao, J, Valente, EM, Defazio, G, Petrucci, S, Gigante, AF, Rudzińska-Bar, M, Wszolek, ZK, Kennelly, K, Uitti, RJ, Van Gerpen, JA, Hedera, P, Trimble, EJ & Ledoux, MS 2018, 'Whole-exome sequencing for variant discovery in blepharospasm', Molecular Genetics and Genomic Medicine. https://doi.org/10.1002/mgg3.411
Tian, Jun ; Vemula, Satya R. ; Xiao, Jianfeng ; Valente, Enza Maria ; Defazio, Giovanni ; Petrucci, Simona ; Gigante, Angelo Fabio ; Rudzińska-Bar, Monika ; Wszolek, Zbigniew K ; Kennelly, Kathleen ; Uitti, Ryan J. ; Van Gerpen, Jay A ; Hedera, Peter ; Trimble, Elizabeth J. ; Ledoux, Mark S. / Whole-exome sequencing for variant discovery in blepharospasm. In: Molecular Genetics and Genomic Medicine. 2018.
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abstract = "Background: Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation. Methods: We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis. Results: Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia. Conclusions: Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.",
keywords = "Blepharospasm, Cerebellum, Dystonia, Purkinje cell, Whole-exome sequencing",
author = "Jun Tian and Vemula, {Satya R.} and Jianfeng Xiao and Valente, {Enza Maria} and Giovanni Defazio and Simona Petrucci and Gigante, {Angelo Fabio} and Monika Rudzińska-Bar and Wszolek, {Zbigniew K} and Kathleen Kennelly and Uitti, {Ryan J.} and {Van Gerpen}, {Jay A} and Peter Hedera and Trimble, {Elizabeth J.} and Ledoux, {Mark S.}",
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T1 - Whole-exome sequencing for variant discovery in blepharospasm

AU - Tian, Jun

AU - Vemula, Satya R.

AU - Xiao, Jianfeng

AU - Valente, Enza Maria

AU - Defazio, Giovanni

AU - Petrucci, Simona

AU - Gigante, Angelo Fabio

AU - Rudzińska-Bar, Monika

AU - Wszolek, Zbigniew K

AU - Kennelly, Kathleen

AU - Uitti, Ryan J.

AU - Van Gerpen, Jay A

AU - Hedera, Peter

AU - Trimble, Elizabeth J.

AU - Ledoux, Mark S.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation. Methods: We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis. Results: Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia. Conclusions: Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.

AB - Background: Blepharospasm (BSP) is a type of focal dystonia characterized by involuntary orbicularis oculi spasms that are usually bilateral, synchronous, and symmetrical. Despite strong evidence for genetic contributions to BSP, progress in the field has been constrained by small cohorts, incomplete penetrance, and late age of onset. Although several genetic etiologies for dystonia have been identified through whole-exome sequencing (WES), none of these are characteristically associated with BSP as a singular or predominant manifestation. Methods: We performed WES on 31 subjects from 21 independent pedigrees with BSP. The strongest candidate sequence variants derived from in silico analyses were confirmed with bidirectional Sanger sequencing and subjected to cosegregation analysis. Results: Cosegregating deleterious variants (GRCH37/hg19) in CACNA1A (NM_001127222.1: c.7261_7262delinsGT, p.Pro2421Val), REEP4 (NM_025232.3: c.109C>T, p.Arg37Trp), TOR2A (NM_130459.3: c.568C>T, p.Arg190Cys), and ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) were identified in four independent multigenerational pedigrees. Deleterious variants in HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) and GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) were identified in a father and son with segmental cranio-cervical dystonia first manifest as BSP. Deleterious variants in DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, and MRPL15 were found in two or more independent pedigrees. To our knowledge, none of these genes have previously been associated with isolated BSP, although other CACNA1A mutations have been associated with both positive and negative motor disorders including ataxia, episodic ataxia, hemiplegic migraine, and dystonia. Conclusions: Our WES datasets provide a platform for future studies of BSP genetics which will demand careful consideration of incomplete penetrance, pleiotropy, population stratification, and oligogenic inheritance patterns.

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KW - Cerebellum

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KW - Purkinje cell

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