REEP4 variant analysis in blepharospasm and other neurological disorders

TL;DR

This study investigates the role of REEP4 gene variants in blepharospasm and related neurological disorders, finding that highly harmful variants are rare in these conditions.

Contribution

The study provides new evidence that highly deleterious REEP4 variants are uncommon in blepharospasm and BSP+ phenotypes.

Findings

No highly deleterious REEP4 variants were found in 307 subjects with blepharospasm or BSP+.

In silico analysis revealed many deleterious REEP4 variants in dystonia studies and ClinVar.

Highly deleterious REEP4 variants are rare in blepharospasm and related disorders.

Abstract

In preceding work, a deleterious REEP4 variant [GRCh38/hg38, NC_000008.11:g.22140245G>A, NM_025232.4:c.109C>T, p.Arg37Trp] was found to co-segregate with blepharospasm (BSP) in a large African-American pedigree. Other REEP4 variants have been reported in genetic screening studies of dystonia. The REEP4 paralogs, REEP1 and REEP2, are associated with spastic paraplegia. The causal contributions of REEP4 variants to dystonia and other neurological disorders remains indecisive.

Sanger sequencing was used to screen subjects (N = 307) with BSP and BSP-plus dystonia affecting additional anatomical segments (BSP+) phenotypes for variants in REEP4. In silico tools were used to examine the deleteriousness of reported (ClinVar) and previously published REEP4 variants.

No highly deleterious variant was identified in coding or contiguous splice site regions of REEP4 in our cohort of 307 subjects. In silico analysis identified numerous deleterious REEP4 variants in published screening studies of dystonia and several highly deleterious single nucleotide REEP4 variants in ClinVar.

Highly deleterious REEP4 variants are rare in BSP and BSP+ phenotypes.