Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions

Katherine S. Josephs, Angharad M. Roberts, Pantazis Theotokis, Roddy Walsh, Philip J. Ostrowski, Matthew Edwards, Andrew Fleming, Courtney Thaxton, Jason D. Roberts, Melanie Care, Wojciech Zareba, Arnon Adler, Amy C. Sturm, Rafik Tadros, Valeria Novelli, Emma Owens, Lucas Bronicki, Olga Jarinova, Bert Callewaert, Stacey PetersTom Lumbers, Elizabeth Jordan, Babken Asatryan, Neesha Krishnan, Ray E. Hershberger, C. Anwar A. Chahal, Andrew P. Landstrom, Cynthia James, Elizabeth M. McNally, Daniel P. Judge, Peter van Tintelen, Arthur Wilde, Michael Gollob, Jodie Ingles, James S. Ware*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including secondary findings. Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results: For 36/65 gene-disease pairs, loss of function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using the CardiacG2P dataset as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is a pre-requisite for scalable genomic testing.

Original languageEnglish (US)
Article number86
JournalGenome Medicine
Volume15
Issue number1
DOIs
StatePublished - Dec 2023

Keywords

  • Allelic requirement
  • Disease mechanism
  • Gene curation
  • Genomic variant filtering
  • Inheritance
  • Inherited cardiac conditions
  • Variant classification
  • Variant interpretation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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