PT  - JOURNAL ARTICLE
AU  - Robak, Laurie A.
AU  - Du, Renqian
AU  - Yuan, Bo
AU  - Gu, Shen
AU  - Alfradique-Dunham, Isabel
AU  - Kondapalli, Vismaya
AU  - Hinojosa, Evelyn
AU  - Stillwell, Amanda
AU  - Young, Emily
AU  - Zhang, Chaofan
AU  - Song, Xiaofei
AU  - Du, Haowei
AU  - Gambin, Tomasz
AU  - Jhangiani, Shalini N.
AU  - Coban Akdemir, Zeynep
AU  - Muzny, Donna M.
AU  - Tejomurtula, Anusha
AU  - Ross, Owen A.
AU  - Shaw, Chad
AU  - Jankovic, Joseph
AU  - Bi, Weimin
AU  - Posey, Jennifer E.
AU  - Lupski, James R.
AU  - Shulman, Joshua M.
TI  - Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease
AID  - 10.1212/NXG.0000000000000498
DP  - 2020 Oct 01
TA  - Neurology Genetics
PG  - e498
VI  - 6
IP  - 5
4099  - http://ng.neurology.org/content/6/5/e498.short
4100  - http://ng.neurology.org/content/6/5/e498.full
SO  - Neurol Genet2020 Oct 01; 6
AB  - 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.aCGH=array-based comparative genomic hybridization; BCM=Baylor College of Medicine; CNV=copy number variant; ddPCR=droplet digital PCR; DUP-TRP/INV-DUP=duplication-inverted triplication-duplication; ES=exome sequencing; FoSTeS=fork stalling and template switching; MMBIR=microhomology-mediated break-induced replication; OR=odds ratio; PD=Parkinson disease; SNV=single nucleotide variant; VUS=variant of unknown significance