Integrated Sequencing &amp; Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

Robak, Laurie; Du, Renqian; Yuan, Bo; Gu, Shen; Alfradique-Dunham, Isabel; Kondapalli, Vismaya; Hinojosa, Evelyn; Stillwell, Amanda; Young, Emily; Zhang, C.; Song, Xiaofei; Du, Huilong; Gambin, Tomasz; Jhangiani, Shalini N.; Akdemir, Zeynep Coban; Tejomurtula, Anusha; Ross, Owen A.; Shaw, Chad A.; Jankovic, Joseph; Bi, Weimin; Posey, Jennifer E.; Lupski, James R.; Liu, Zhandong

doi:10.1101/828566

Cited by 3 publications

(7 citation statements)

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“…Furthermore, the frequencies of variants in LRRK2 , GBA , and PRKN are comparable to findings from previous screening studies targeting these 3 genes in single cohorts 3,15,16 . As in the aforementioned reports, p.Gly2019Ser is the most frequent LRRK2 variant and p.Glu365Lys and p.Thr408Met are the most prevalent GBA alleles 15,16 . Notably, we have confirmed the observation that some patients might harbor variants in both LRRK2 and GBA 15 .…”

Section: Discussionsupporting

confidence: 89%

“…As in the aforementioned reports, p.Gly2019Ser is the most frequent LRRK2 variant and p.Glu365Lys and p.Thr408Met are the most prevalent GBA alleles 15,16 . Notably, we have confirmed the observation that some patients might harbor variants in both LRRK2 and GBA 15 . The PRKN and SNCA CNVs in our patient cohort highlight the importance of a CNV pipeline, which is often not included in the analysis of gene panel sequencing data in other studies.…”

Section: Discussionsupporting

confidence: 88%

“…15,16 Notably, we have confirmed the observation that some patients might harbor variants in both LRRK2 and GBA. 15 The PRKN and SNCA CNVs in our patient cohort highlight the importance of a CNV pipeline, which is often not included in the analysis of gene panel sequencing data in other studies. As expected, GBA and PRKN variants were associated with lower AAO in our preliminary patient cohort, 17,18 whereas AAOs of patients with LRRK2 alterations were comparable to those without monogenic PD cause.…”

Section: Discussionsupporting

confidence: 85%

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The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings

et al. 2020

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Background Genetic stratification of Parkinson's disease (PD) patients facilitates gene‐tailored research studies and clinical trials. The objective of this study was to describe the design of and the initial data from the Rostock International Parkinson's Disease (ROPAD) study, an epidemiological observational study aiming to genetically characterize ~10,000 participants. Methods Recruitment criteria included (1) clinical diagnosis of PD, (2) relative of participant with a reportable LRRK2 variant, or (3) North African Berber or Ashkenazi Jew. DNA analysis involved up to 3 successive steps: (1) variant (LRRK2) and gene (GBA) screening, (2) panel sequencing of 68 PD‐linked genes, and (3) genome sequencing. Results Initial data based on the first 1360 participants indicated that the ROPAD enrollment strategy revealed a genetic diagnostic yield of ~14% among a PD cohort from tertiary referral centers. Conclusions The ROPAD screening protocol is feasible for high‐throughput genetic characterization of PD participants and subsequent prioritization for gene‐focused research efforts and clinical trials. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 85%

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The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings

et al. 2020

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“…Still, the role of heterozygous PRKN CNVs in altering PD susceptibility remains controversial 16,52 . To correctly characterize PD patients, an integrated SNV‐CNV analysis is needed, given the importance of both allele types for comprehensive genetic diagnosis in PD 53 . Our sequencing of the entire PRKN coding region for all 26 PRKN CNV carriers identified that 5 of the 20 patients also carried a pathogenic SNV, whereas none of the 6 controls did.…”

Section: Discussionmentioning

confidence: 99%

Genome‐Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients

et al. 2020

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Background Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non‐European populations. In addition, the overall identification of copy number variants at a genome‐wide level has been understudied in Parkinson's patients. The objective of this study was to understand the genome‐wide burden of copy number variants in Latinos and its association with Parkinson's disease. Methods We used genome‐wide genotyping data from 747 Parkinson's disease patients and 632 controls from the Latin American Research Consortium on the Genetics of Parkinson's disease. Results Genome‐wide copy number burden analysis showed that patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared with controls (odds ratio, 3.97; 95%CI, 1.69–10.5; P = 0.018). PRKN showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared with patients with other copy number variants (median age at onset, 31 vs 57 years, respectively; P = 7.46 × 10−7). Conclusions We found that although overall genome‐wide copy number variant burden was not significantly different, Parkinson's disease patients were significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that of 250 patients with early‐onset disease, 5.6% carried a copy number variant on PRKN in our cohort. Our study is the first to analyze genome‐wide copy number variant association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population. © 2020 International Parkinson and Movement Disorder Society

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“…Still, the role of heterozygous PARK2 CNVs in altering PD susceptibility remains controversial 16,52 . In order to correctly characterize PD patients, an integrated SNV-CNV analysis is needed, given the importance of both allele types for comprehensive genetic diagnosis in PD 53 . Pankratz et al showed that the frequency of carrying a single PARK2 CNV was higher in PD patients compared to controls, while it was similar for carrying a single point mutation 54 Heterozygous PARK2 CNV carrier status may still play a role in the development of PD despite its recessive inheritance 46,55 , through a haploinsufficiency effect 56 .…”

Section: Discussionmentioning

confidence: 99%

Genome-wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients

Sarihan

Pérez‐Palma

Niestroj

et al. 2020

Preprint

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Background: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's disease patients. Objectives: To understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease. Methods: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 ancestry matched controls from the Latin American Research Consortium on the Genetics of Parkinson's disease. Results: Genome-wide copy number burden analysis showed no difference between patients vs. controls, whereas patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared to controls (Odds Ratio: 3.97 [1.69 - 10.5], P = 0.018). PARK2 showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared to patients with other copy number variants (median age at onset: 31 years vs. 57 years, P = 7.46 x 10-7). Conclusions: We found that Parkinson's disease patients are significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that out of 250 patients with early-onset disease, 5.6% carried a copy number variant on PARK2 in our cohort. Our study is the first to analyze genome-wide copy number variants association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population.

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Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

Cited by 3 publications

References 93 publications

The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings

The Rostock International Parkinson's Disease (ROPAD) Study: Protocol and Initial Findings

Genome‐Wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients

Genome-wide Analysis of Copy Number Variation in Latin American Parkinson's Disease Patients

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