Reassessment Of Mendelian Gene Pathogenicity Using 7,855 Cardiomyopathy Cases And 60,706 Reference Samples

By R. Walsh, K. Thomson, J. Ware, Birgit Funke, Jessica Woodley, K. McGuire, F. Mazzarotto, E. Blair, A. Seller, Jenny C. Taylor and 5 more. Genetics in Medicine, 2016

703 citations recorded by the source corpus.

Purpose:The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but they also provide an invaluable opportunity to characterize the spectrum and importance of rare variation.Methods:We analyzed sequence data from 7,855 clinical cardiomyopathy cases and 60,706 Exome Aggregation Consortium (ExAC) reference samples to obtain a better understanding of genetic variation in a representative autosomal dominant disorder.Results:We found that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative because there is an unacceptably high likelihood of false-positive interpretation. By contrast, in other genes, we find that diagnostic laboratories may be overly conservative when assessing variant pathogenicity.Conclusions:We outline improved analytical approaches that evaluate which genes and variant classes are interpretable and propose that these will increase the clinical utility of testing across a range of Mendelian diseases.Genet Med 19 2, 192–203.

Subfields: Cardiology and Cardiovascular Medicine, Genetics

View Paper: https://www.semanticscholar.org/paper/ddf7588d899f99000ec38168331b12435072c315

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Citations in the corpus

Variant interpretation using population databases: lessons from gnomAD (2021, background): “ease genes (Walsh et al., 2017), and determination of the penetrance of dominant disease variants (Minikel et al.”
2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. (2019, background): “Gene Protein Type Predominant Type of Mutation OR/EF (100) Signal: Background (94) Remarks References”
Dilated Cardiomyopathy: Genetic Determinants and Mechanisms (2017, neutral): “There is considerable genetic heterogeneity in the SCN5A gene in the general population, making it challenging to interpret rare variation in the SCN5A gene.(62) Genotype–phenotype association studies may guide genotype-based therapies.”
The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies (2017, positive): “In a clinical setting, HGMD is widely utilised by many groups in ongoing NGS diagnostic (Bell et al. 2011; Johnston et al. 2012; Calvo et al. 2012; Makrythanasis et al. 2014; Karageorgos et al. 2015; Wilfert et al. 2016; Walsh et al. 2017) and human genome sequencing (Tong et al.”
Adaptation and Validation of the ACMG/AMP variant classification framework for MYH7-associated inherited cardiomyopathies: Recommendations by ClinGen’s Inherited Cardiomyopathy Expert Panel (2018, positive): “However, recent studies suggest that this is driven by statistically significant clustering of pathogenic variants in the head region (p 3×10 −15 , amino acids 181 – 937, NM_000257) 23,24 .”
Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. (2017, methodology): “Evidence for the causal role of the above 9 genes in HCM is the strongest (Table 1).(32,33) Mutations in TTN (titin), TCAP (telethonin), MYOZ2 (myozenin 2), TRIM63 (ubiquitin E3 ligase tripartite motif protein 63 or MuRF1), and FHL1 (four-and-a-half LIM domains 1) also have been implicated as causes”