Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease
| Autor: | Vismaya Kondapalli, Evelyn Hinojosa, Owen A. Ross, Chuansheng Zhang, Jennifer E. Posey, Anusha Tejomurtula, Renqian Du, Amanda Stillwell, Isabel Alfradique-Dunham, Xianzhou Song, Tomaz Gambin, Weimin Bi, Emily Young, James R. Lupski, Shalini N. Jhangiani, Shen Gu, Haowei Du, Joseph Jankovic, Joshua M. Shulman, Donna M. Muzny, Laurie Robak, Chad A. Shaw, Bo Yuan, Z. Coban Akdemir |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
2. Zero hunger
Genetics Sanger sequencing 0303 health sciences Genetic heterogeneity Locus (genetics) Biology Compound heterozygosity 3. Good health 03 medical and health sciences symbols.namesake 0302 clinical medicine symbols Digital polymerase chain reaction Copy-number variation 030217 neurology & neurosurgery Exome sequencing 030304 developmental biology Comparative genomic hybridization |
| DOI: | 10.1101/828566 |
| Popis: | BackgroundParkinson’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.MethodsWe 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.ResultsUsing 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.ConclusionsIntegrated 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. |
| Databáze: | OpenAIRE |
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