RT Journal Article
SR Electronic
T1 Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 828566
DO 10.1101/828566
A1 Laurie A. Robak
A1 Renqian Du
A1 Bo Yuan
A1 Shen Gu
A1 Isabel Alfradique-Dunham
A1 Vismaya Kondapalli
A1 Evelyn Hinojosa
A1 Amanda Stillwell
A1 Emily Young
A1 Chaofan Zhang
A1 Xiaofei Song
A1 Haowei Du
A1 Tomasz Gambin
A1 Shalini N. Jhangiani
A1 Zeynep Coban Akdemir
A1 Donna M. Muzny
A1 Anusha Tejomurtula
A1 Owen A. Ross
A1 Chad Shaw
A1 Joseph Jankovic
A1 Weimin Bi
A1 Jennifer E. Posey
A1 James R. Lupski
A1 Joshua M. Shulman
YR 2019
UL http://biorxiv.org/content/early/2019/11/11/828566.abstract
AB Background Parkinson’s disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors. We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors.Methods We performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing.Results Using exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). 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.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 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 exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.