Abstract
BackgroundBlepharospasm (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.MethodsWe 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.ResultsCosegregating 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.ConclusionsOur 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.
Highlights
Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both (Albanese et al, 2013)
All human studies were conducted in accordance with the Declaration of Helsinki with formal approval from the University of Tennessee Health Science Center Institutional Review Board (IRB; 01-07346-FB, 05-08331-XP, and 1403320-XP) and ethics committees of all participating centers
CNVkit (Talevich, Shain, Botton, & Bastian, 2016), a Python library and command-line software toolkit to infer and visualize copy number variants (CNVs) from targeted DNA sequencing data, was used to detect CNVs in whole-exome sequencing (WES) data generated by Otogenetics on the Illumina platform
Summary
Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both (Albanese et al, 2013). In six published clinical series, 1st-degree relatives of probands with isolated dystonia were subjected to examination Discordant pedigrees are relatively more common in probands with BSP than cervical dystonia (Defazio, Berardelli, & Hallett, 2007). We report the results of whole-exome sequencing (WES) of 31 subjects from 21 independent pedigrees with BSP and/or BSP+, the largest collection of BSP pedigrees examined to date. Our series includes both concordant and discordant pedigrees. Cosegregating deleterious variants in CACNA1A (OMIM 601011), REEP4 (OMIM 609349), TOR2A (OMIM 608052), ATP2A3 (OMIM 601929), HS1BP3 (OMIM 609359), GNA14 (OMIM 604397) and DNAH17 (OMIM 610063) were identified in single pedigrees
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