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    Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.

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    Author
    Farlow, JL; Lin, H; Sauerbeck, L; Lai, D; Koller, DL; Pugh, E; Hetrick, K; Ling, H; Kleinloog, R; van der Vlies, P; ...
    Date
    2015
    Source Title
    PLoS One
    Publisher
    Public Library of Science (PLoS)
    University of Melbourne Author/s
    Laidlaw, John
    Affiliation
    Surgery (RMH)
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Farlow, J. L., Lin, H., Sauerbeck, L., Lai, D., Koller, D. L., Pugh, E., Hetrick, K., Ling, H., Kleinloog, R., van der Vlies, P., Deelen, P., Swertz, M. A., Verweij, B. H., Regli, L., Rinkel, G. J. E., Ruigrok, Y. M., Doheny, K., Liu, Y., Broderick, J. ,... FIA Study Investigators (2015). Lessons learned from whole exome sequencing in multiplex families affected by a complex genetic disorder, intracranial aneurysm.. PLoS One, 10 (3), pp.e0121104-. https://doi.org/10.1371/journal.pone.0121104.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/256356
    DOI
    10.1371/journal.pone.0121104
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372548
    Abstract
    Genetic risk factors for intracranial aneurysm (IA) are not yet fully understood. Genomewide association studies have been successful at identifying common variants; however, the role of rare variation in IA susceptibility has not been fully explored. In this study, we report the use of whole exome sequencing (WES) in seven densely-affected families (45 individuals) recruited as part of the Familial Intracranial Aneurysm study. WES variants were prioritized by functional prediction, frequency, predicted pathogenicity, and segregation within families. Using these criteria, 68 variants in 68 genes were prioritized across the seven families. Of the genes that were expressed in IA tissue, one gene (TMEM132B) was differentially expressed in aneurysmal samples (n=44) as compared to control samples (n=16) (false discovery rate adjusted p-value=0.023). We demonstrate that sequencing of densely affected families permits exploration of the role of rare variants in a relatively common disease such as IA, although there are important study design considerations for applying sequencing to complex disorders. In this study, we explore methods of WES variant prioritization, including the incorporation of unaffected individuals, multipoint linkage analysis, biological pathway information, and transcriptome profiling. Further studies are needed to validate and characterize the set of variants and genes identified in this study.

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