Whole-exome sequencing for variant discovery in blepharospasm.

Autor: Tian J; Departments of Neurology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee.; Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China., Vemula SR; Departments of Neurology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee., Xiao J; Departments of Neurology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee., Valente EM; Department of Molecular Medicine, University of Pavia, Pavia, Italy.; Neurogenetics Unit, IRCCS Santa Lucia Foundation, Rome, Italy., Defazio G; Department of Basic Clinical Sciences, Neuroscience and Sense Organs, Aldo Moro University of Bari, Bari, Italy.; Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy., Petrucci S; Department of Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy., Gigante AF; Department of Basic Clinical Sciences, Neuroscience and Sense Organs, Aldo Moro University of Bari, Bari, Italy., Rudzińska-Bar M; Department of Neurology, Faculty of Medicine, Medical University of Silesia, Katowice, Poland., Wszolek ZK; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida., Kennelly KD; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida., Uitti RJ; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida., van Gerpen JA; Department of Neurology, Mayo Clinic Florida, Jacksonville, Florida., Hedera P; Department of Neurology, Vanderbilt University, Nashville, Tennessee., Trimble EJ; Departments of Neurology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee., LeDoux MS; Departments of Neurology and Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee.
Jazyk: angličtina
Zdroj: Molecular genetics & genomic medicine [Mol Genet Genomic Med] 2018 May 16. Date of Electronic Publication: 2018 May 16.
DOI: 10.1002/mgg3.411
Abstrakt: 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.
(© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)
Databáze: MEDLINE
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