Open AccessTargeted copy number variant identification across the neurodegenerative disease spectrum
Author(s) -
Dilliott Allison A.,
Zhang Kristina K.,
Wang Jian,
Abrahao Agessandro,
Binns Malcolm A.,
Black Sandra E.,
Borrie Michael,
Dowlatshahi Dar,
Finger Elizabeth,
Fischer Corinne E.,
Frank Andrew,
Freedman Morris,
Grimes David,
Hassan Ayman,
Jog Mandar,
Kumar Sanjeev,
Lang Anthony E.,
Mandzia Jennifer,
Masellis Mario,
Pasternak Stephen H.,
Pollock Bruce G.,
Rajji Tarek K.,
Rogaeva Ekaterina,
Sahlas Demetrios J.,
Saposnik Gustavo,
Sato Christine,
Seitz Dallas,
Shoesmith Christen,
Steeves Thomas D. L.,
Swartz Richard H.,
Tan Brian,
TangWai David F.,
Tartaglia Maria C.,
Turnbull John,
Zinman Lorne,
Hegele Robert A.
Publication year - 2022
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1986
Subject(s) - copy number variation , gene duplication , disease , missing heritability problem , genetics , amyotrophic lateral sclerosis , biology , exon , neurodegeneration , medicine , gene , single nucleotide polymorphism , genome , pathology , genotype
Background Although genetic factors are known to contribute to neurodegenerative disease susceptibility, there remains a large amount of heritability unaccounted for across the diagnoses. Copy number variants (CNVs) contribute to these phenotypes, but their presence and influence on disease state remains relatively understudied. Methods Here, we applied a depth of coverage approach to detect CNVs in 80 genes previously associated with neurodegenerative disease within participants of the Ontario Neurodegenerative Disease Research Initiative ( n = 519). Results In total, we identified and validated four CNVs in the cohort, including: (1) a heterozygous deletion of exon 5 in OPTN in an Alzheimer's disease participant; (2) a duplication of exons 1–5 in PARK7 in an amyotrophic lateral sclerosis participant; (3) a duplication of >3 Mb, which encompassed ABCC6 , in a cerebrovascular disease (CVD) participant; and (4) a duplication of exons 7–11 in SAMHD1 in a mild cognitive impairment participant. We also identified 43 additional CNVs that may be candidates for future replication studies. Conclusion The identification of the CNVs suggests a portion of the apparent missing heritability of the phenotypes may be due to these structural variants, and their assessment is imperative for a thorough understanding of the genetic spectrum of neurodegeneration.