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. 2022 Aug;43(8):1031-1040.
doi: 10.1002/humu.24291. Epub 2021 Nov 15.

Utilizing ClinGen gene-disease validity and dosage sensitivity curations to inform variant classification

Courtney Thaxton  1 , Molly E Good  2 , Marina T DiStefano  3 , Xi Luo  4 , Erica F Andersen  5   6 , Erik Thorland  7 , Jonathan Berg  1 , Christa Lese Martin  2 , Heidi L Rehm  8 , Erin R Riggs  2 ; ClinGen Gene Curation Working Group; ClinGen Dosage Sensitivity Working Group
Affiliations

Utilizing ClinGen gene-disease validity and dosage sensitivity curations to inform variant classification

Courtney Thaxton et al. Hum Mutat. 2022 Aug.

Abstract

Understanding whether there is enough evidence to implicate a gene's role in a given disease, as well as the mechanisms by which variants in this gene might cause this disease, is essential to determine clinical relevance. The National Institutes of Health-funded Clinical Genome Resource (ClinGen) has developed evaluation frameworks to assess both the strength of evidence supporting a relationship between a gene and disease (gene-disease validity), and whether loss (haploinsufficiency) or gain (triplosensitivity) of individual genes or genomic regions is a mechanism for disease (dosage sensitivity). ClinGen actively applies these frameworks across multiple disease domains, and makes this information publicly available via its website (https://www.clinicalgenome.org/) for use in multiple applications, including clinical variant classification. Here, we describe how the results of these curation processes can be utilized to inform the appropriate application of pathogenicity criteria for both sequence and copy number variants, as well as to guide test development and inform genomic filtering pipelines.

Keywords: dosage sensitivity; gene panels; gene-disease validity; genetic testing; variant interpretation; variant pathogenicity.

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Conflict of interest statement

Conflict of Interest: The authors have no conflicts to disclose.

Figures

Figure 1:
Figure 1:
Summary of ClinGen’s gene-disease validity classifications as of April 2021 (n=1261 gene-disease pairs).
Figure 2:
Figure 2:
Summary of ClinGen’s dosage sensitivity scores as of April 2021. Each gene or genomic region evaluated (n=1537) receives a haploinsufficiency score (A) and a separate triplosensitivity score (B).
Figure 3:
Figure 3:
Overlap in single genes evaluated by ClinGen gene-disease validity and dosage sensitivity curation. As of April 2021, 1045 genes had been evaluated for gene-disease validity, and 1463 single genes had been evaluated for dosage sensitivity, with 512 genes evaluated by both groups. These numbers do not include dosage sensitivity evaluations for genomic regions or with multiple gene-disease validity curations per gene.
Figure 4:
Figure 4:
Summary of genes included on clinical next-generation sequencing panels targeted for hypertrophic cardiomyopathy as registered in the Genetic Testing Registry as of April 2021.
See this image and copyright information in PMC

References

    1. Abou Tayoun AN, Pesaran T, DiStefano MT, Oza A, Rehm HL, Biesecker LG, … ClinGen Sequence Variant Interpretation Working Group (ClinGen, SVI). (2018). Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Human Mutation, 39(11), 1517–1524. doi:10.1002/humu.23626 [doi] - DOI - PMC - PubMed
    1. Andreasen C, Nielsen JB, Refsgaard L, Holst AG, Christensen AH, Andreasen L, … Olesen MS (2013). New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants. European Journal of Human Genetics : EJHG, 21(9), 918–928. doi:10.1038/ejhg.2012.283 [doi] - DOI - PMC - PubMed
    1. Bean LJH, Funke B, Carlston CM, Gannon JL, Kantarci S, Krock BL, … ACMG Laboratory Quality Assurance Committee. (2020). Diagnostic gene sequencing panels: From design to report-a technical standard of the american college of medical genetics and genomics (ACMG). Genetics in Medicine : Official Journal of the American College of Medical Genetics, 22(3), 453–461. doi:10.1038/s41436-019-0666-z [doi] - DOI - PubMed
    1. Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD, … Bamshad MJ (2015). The genetic basis of mendelian phenotypes: Discoveries, challenges, and opportunities. American Journal of Human Genetics, 97(2), 199–215. doi:S0002–9297(15)00245–1 [pii] - PMC - PubMed
    1. Claussnitzer M, Cho JH, Collins R, Cox NJ, Dermitzakis ET, Hurles ME, … McCarthy MI (2020). A brief history of human disease genetics. Nature, 577(7789), 179–189. doi:10.1038/s41586-019-1879-7 [doi] - DOI - PMC - PubMed

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