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Objective  To determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms.    Methods  We performed ES on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated ES and aCGH data for pathogenic SNVs and CNVs at Mendelian PD gene loci. We confirmed SNVs via Sanger sequencing and further characterized CNVs with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing.    Results  Using ES, we discovered individuals with known pathogenic SNVs in  GBA  (p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and  LRRK2  (p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in  GBA  and  LRRK2 . Based on aCGH, we additionally discovered cases with an  SNCA  duplication and heterozygous intragenic  GBA  deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the  PRKN  locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors.    Conclusions  Integrated ES and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for  SNCA  and  PRKN  CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease