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

Publication ,  Journal Article
Josephs, KS; Roberts, AM; Theotokis, P; Walsh, R; Ostrowski, PJ; Edwards, M; Fleming, A; Thaxton, C; Roberts, JD; Care, M; Zareba, W; Adler, A ...
Published in: Genome Med
October 23, 2023

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.

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Published In

Genome Med

DOI

EISSN

1756-994X

Publication Date

October 23, 2023

Volume

15

Issue

1

Start / End Page

86

Location

England

Related Subject Headings

  • Inheritance Patterns
  • Humans
  • Genomics
  • Genetic Variation
  • Genetic Testing
  • Databases, Genetic
  • 3105 Genetics
  • 1103 Clinical Sciences
  • 0604 Genetics
 

Citation

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Josephs, K. S., Roberts, A. M., Theotokis, P., Walsh, R., Ostrowski, P. J., Edwards, M., … Ware, J. S. (2023). Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions. Genome Med, 15(1), 86. https://doi.org/10.1186/s13073-023-01246-8
Josephs, Katherine S., Angharad M. Roberts, Pantazis Theotokis, Roddy Walsh, Philip J. Ostrowski, Matthew Edwards, Andrew Fleming, et al. “Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.Genome Med 15, no. 1 (October 23, 2023): 86. https://doi.org/10.1186/s13073-023-01246-8.
Josephs, Katherine S., et al. “Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.Genome Med, vol. 15, no. 1, Oct. 2023, p. 86. Pubmed, doi:10.1186/s13073-023-01246-8.
Josephs KS, Roberts AM, Theotokis P, Walsh R, Ostrowski PJ, Edwards M, Fleming A, Thaxton C, Roberts JD, Care M, Zareba W, Adler A, Sturm AC, Tadros R, Novelli V, Owens E, Bronicki L, Jarinova O, Callewaert B, Peters S, Lumbers T, Jordan E, Asatryan B, Krishnan N, Hershberger RE, Chahal CAA, Landstrom AP, James C, McNally EM, Judge DP, van Tintelen P, Wilde A, Gollob M, Ingles J, Ware JS. Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions. Genome Med. 2023 Oct 23;15(1):86.
Journal cover image

Published In

Genome Med

DOI

EISSN

1756-994X

Publication Date

October 23, 2023

Volume

15

Issue

1

Start / End Page

86

Location

England

Related Subject Headings

  • Inheritance Patterns
  • Humans
  • Genomics
  • Genetic Variation
  • Genetic Testing
  • Databases, Genetic
  • 3105 Genetics
  • 1103 Clinical Sciences
  • 0604 Genetics