Whole-exome sequencing for variant discovery in blepharospasm

摘要: 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 small cohorts, incomplete penetrance, late age onset. Although several etiologies have identified through whole-exome sequencing (WES), none these characteristically associated with BSP as singular or predominant manifestation. Methods We performed WES on 31 subjects from 21 independent pedigrees BSP. The strongest candidate sequence variants derived silico analyses were confirmed bidirectional Sanger subjected cosegregation analysis. Results Cosegregating deleterious (GRCH37/hg19) 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), ATP2A3 (NM_005173.3: c.1966C>T, p.Arg656Cys) four multigenerational pedigrees. Deleterious HS1BP3 (NM_022460.3: c.94C>A, p.Gly32Cys) GNA14 (NM_004297.3: c.989_990del, p.Thr330ArgfsTer67) father son segmental cranio-cervical first manifest DNAH17, TRPV4, CAPN11, VPS13C, UNC13B, SPTBN4, MYOD1, MRPL15 found two more To our knowledge, genes previously isolated although other mutations both positive negative motor disorders including ataxia, episodic hemiplegic migraine, dystonia. Conclusions Our datasets provide platform future studies genetics which will demand careful consideration pleiotropy, population stratification, oligogenic inheritance patterns.