Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease.

TitleIntegrated sequencing and array comparative genomic hybridization in familial Parkinson disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsRobak, LA, Du, R, Yuan, B, Gu, S, Alfradique-Dunham, I, Kondapalli, V, Hinojosa, E, Stillwell, A, Young, E, Zhang, C, Song, X, Du, H, Gambin, T, Jhangiani, SN, Akdemir, ZCoban, Muzny, DM, Tejomurtula, A, Ross, OA, Shaw, C, Jankovic, J, Bi, W, Posey, JE, Lupski, JR, Shulman, JM
JournalNeurol Genet
Volume6
Issue5
Paginatione498
Date Published2020 Oct
ISSN2376-7839
Abstract

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 (p.Glu365Lys, p.Thr408Met, p.Asn409Ser, and p.Leu483Pro) and (p.Arg1441Gly and p.Gly2019Ser). Two subjects were each double heterozygotes for variants in and . Based on aCGH, we additionally discovered cases with an duplication and heterozygous intragenic deletion. Five additional subjects harbored both SNVs (p.Asn52Metfs*29, p.Thr240Met, p.Pro437Leu, and p.Trp453*) and likely disrupting CNVs at the 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 and CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

DOI10.1212/NXG.0000000000000498
Alternate JournalNeurol Genet
PubMed ID32802956
PubMed Central IDPMC7413630