A comprehensive analysis of dominant and recessive parkinsonism genes in REM sleep behavior disorder

Abstract

AbstractObjectiveTo examine the role of autosomal dominant (AD) and recessive (AR) Parkinsonism genes in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).MethodsTen genes implicated in AD and AR Parkinsonism were fully sequenced using targeted next-generation sequencing in 1,039 iRBD patients and 1,852 controls of European ancestry. These include the AR genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7 and PLA2G6, and the AD genes LRRK2, GCH1 and VPS35. To examine the role of rare heterozygous variants in these genes, burden test and SKAT-O analyses were performed. The contribution of homozygous and compound heterozygous variants was further examined in the AR genes. Copy number variants (CNVs) in PRKN were tested in a subset of samples (n=374) using multiplex ligation-dependent probe amplification followed by analysis of all samples using ExomeDepth.ResultsWe found no association between rare heterozygous variants in the tested genes and risk for iRBD. Several homozygous and compound heterozygous carriers were identified with variants of unknown significance, yet there was no overrepresentation in iRBD patients versus controls.ConclusionOur results do not support a major role for variants in PRKN, PARK7, PINK1, VPS13C, ATP13A2, FBXO7, PLA2G6, LRRK2, GCH1 and VPS35 in the risk of iRBD.