Objective: To determine whether whole exome sequencing (WES) plus chromosomal microarray analysis (CMA) yield a genetic etiology in a cohort of 110 individuals with familial Parkinson’s disease (PD).

Background: For genetically complex diseases such as PD, single nucleotide variants (SNVs) and copy number variants (CNVs) are important risk factors. While various methods have been used to evaluate CNVs, none have specifically addressed the utility of combining WES and CMA in PD.

Methods: We studied 110 subjects from our movement disorders clinic with a positive family history of PD (affected first, second, or third degree relative). The mean age at onset was 49.5 years (SD 15.2). WES and CMA were performed on all participants. We interrogated exomes for previously-described SNVs in Mendelian PD genes (SNCA, LRRK2, VPS35, PARK2, GBA, DNAJC13, GCH1, and CHCHD2) and also examined CMA data for CNVs at these loci. SNVs and CNVs were confirmed using Sanger sequencing or a high density customized array CGH, respectively.

Results: Eleven individuals harbored known pathogenic variants in GBA and LRRK2. Seven subjects were heterozygous for SNVs in GBA (p.E365K, p.N370S, p.T408M, p.L444P) and three had SNVs in LRRK2 (p.R1441G and p.G2019S). One subject harbored both GBA p.E365K and LRRK2 p.G2019S. CNV analysis identified a single individual with an SNCA duplication and another subject with a candidate GBA deletion. Five additional subjects harbored both a SNV (3 missense, 1 stopgain, and 1 frameshift) along with a CNV at the PARK2 locus, consistent with compound heterozygosity.

Conclusions: In individuals with familial PD, integrated WES and CMA analysis may yield a higher genetic diagnostic rate than either modality alone, which is primarily due to compound heterozygosity for CNVs and SNVs at PARK2.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/integrated-whole-exome-sequencing-and-chromosomal-microarray-in-familial-parkinsons-disease/