Reducing the search space for causal genetic variants in sequenced pedigrees with VASP — ASN Events
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  3. Reducing the search space for causal genetic variants in sequenced pedigrees with VASP

Reducing the search space for causal genetic variants in sequenced pedigrees with VASP (#166)

Matt A Field 1 2 , Vicky Cho 2 , Matthew Cook 2 , Anselm Enders 2 , Carola Vinuesa 2 , Belinda Whittle 2 , Dan Andrews 2 , Chris Goodnow 3
  1. Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, Qld, Australia
  2. Immunology, Australian National University, Canberra, ACT, Australia
  3. Immunogenomics, Garvan Institute, Sydney, NSW, Australia

Increasingly, cost effective high-throughput DNA sequencing technologies are being utilized to sequence human pedigrees in order to elucidate the genetic cause of a wide variety of human diseases. While numerous tools exist for variant prioritization within a single genome, the ability to concurrently analyze variants within pedigrees remains a challenge, especially should there be no prior indication of the underlying genetic cause of the disease. The effective analysis of sequenced pedigrees requires new tools capable of combining variant specific and pedigree wide annotations with powerful filtering options to dramatically reduce the causal variation search space.

Here, we present variant analysis of sequenced pedigrees (VASP)1, a tool that integrates and summarizes information across a sequenced pedigree without making any assumptions regarding disease inheritance further providing the full integrated pedigree variation information for subsequent prioritization. Within a flexible data integration environment users are able to produce a summary of pedigree variation, providing relevant information such as compound heterozygosity, genome phasing, and disease inheritance patterns. Designed to aggregate data across a sequenced pedigree, VASP allows both powerful filtering and custom prioritization of both SNVs and small indels. Hence, clinical and research users with prior knowledge of a disease are able to dramatically reduce the variant search space based on a wide variety of custom prioritization criteria.

VASP has currently been used to analyze >150 sequenced genome/exome pedigrees and found strong candidate causal variants in roughly 40% of these, resulting in four publications to date2-5. The pedigrees with candidate causal variants exhibit a wide array of disease transmission mechanisms including autosomal dominant and recessive inheritance, de novo mutations, compound heterozygosity and more complex multi-gene cases. This variety in transmission mechanisms within this relatively small group sharing similar diseases illustrates the importance of flexible pedigree analysis software. Source code is available for academic non-commercial research purposes at https://github.com/mattmattmattmatt/VASP

  1. Field MA, Cho V, Cook MC, et al. Reducing the search space for causal genetic variants with VASP: Variant Analysis of Sequenced Pedigrees. Bioinformatics 2015 doi:10.1093/bioinformatics/btv135
  2. Ellyard JI, Jerjen R, Martin JL, et al. Whole exome sequencing in early-onset cerebral SLE identifies a pathogenic variant in TREX1. Arthritis & rheumatology 2014
  3. Lee CE, Fulcher DA, Whittle B, et al. Autosomal dominant B cell deficiency with alopecia due to a mutation in NFKB2 that results in non-processible p100. Blood 2014
  4. Taupin D, Lam W, Rangiah D, et al. A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred. Human Genome Variation 2015;2
  5. Dunkerton S, Field M, Cho V, et al. A de novo mutation in KMT2A (MLL) in monozygotic twins with Wiedemann-Steiner syndrome. Am J Med Genet A 2015.
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