Josephs, Katherine S; Roberts, Angharad M; Theotokis, Pantazis; Walsh, Roddy; Ostrowski, Philip J; Edwards, Matthew; Fleming, Andrew; Thaxton, Courtney; Roberts, Jason D; Care, Melanie; Zareba, Wojciech; Adler, Arnon; Sturm, Amy C; Tadros, Rafik; Novelli, Valeria; Owens, Emma; Bronicki, Lucas; Jarinova, Olga; Callewaert, Bert; Peters, Stacey; ... (2023). Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions. Genome medicine, 15(1), p. 86. BioMed Central 10.1186/s13073-023-01246-8
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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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Department of Cardiovascular Disorders (DHGE) > Clinic of Cardiology |
UniBE Contributor: |
Asatryan, Babken |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1756-994X |
Publisher: |
BioMed Central |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
24 Oct 2023 09:47 |
Last Modified: |
29 Oct 2023 02:26 |
Publisher DOI: |
10.1186/s13073-023-01246-8 |
PubMed ID: |
37872640 |
Uncontrolled Keywords: |
Allelic requirement Disease mechanism Gene curation Genomic variant filtering Inheritance Inherited cardiac conditions Variant classification Variant interpretation |
BORIS DOI: |
10.48350/187397 |
URI: |
https://boris.unibe.ch/id/eprint/187397 |
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