Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

Walsh, Roddy; Thomson, Kate; Ware, James S.; Funke, Birgit; Woodley, Jessica; McGuire, Karen; Mazzarotto, Francesco; Blair, Edward; Seller, A; Taylor, Jenny C.; Minikel, Eric Vallabh; MacArthur, Daniel G.; Farrall, Martin; Cook, Stuart A.; Watkins, Hugh

doi:10.1038/gim.2016.90

Cited by 577 publications

(546 citation statements)

References 42 publications

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“…These associations, however, are based on relatively small series and case reports and in most cases rely on genetic variant classification before the age of large exome databases. Recent studies suggest that some of the genes previously associated with HCM may not have a significant impact on disease expression 11 and that reassessment of variants according to new data results in reclassification in a substantial portion of cases. 12 Moreover, most recent guidelines 13 adopted a much stricter approach for variant classification and are likely to result in some variants previously classified as P/LP to be reclassified as variants of unknown significance (VUS).…”

Section: See Editorial By Fatkin and Johnson See Clinical Perspectivementioning

confidence: 99%

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Fourey

Care

Siminovitch

et al. 2017

Circ Cardiovasc Genet

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Background-Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification. Methods and Results-Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in MYBPC3 in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype-phenotype correlations were scarce. Conclusions-Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical MYBPC3 mutations, there is little data to guide clinical decision making in cases with double mutations. (Circ Cardiovasc

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Section: See Editorial By Fatkin and Johnson See Clinical Perspectivementioning

confidence: 99%

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Fourey

Care

Siminovitch

et al. 2017

Circ Cardiovasc Genet

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“…However, the ExAC Browser is known to include individuals with disease and contain rare pathogenic variants (MAF < 1 3 10 À4 ). 66 Indeed, the TSC2 c.292C>T mutation identified from the blood of TSC individuals is listed in the ExAC Browser (rs372321790; MAF ¼ 2.99 3 10 À5 ). This mutation was previously reported to disrupt TSC2 function and was classified as pathogenic.…”

Section: Discussionmentioning

confidence: 99%

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Lim

Gopalappa

Kim

et al. 2017

The American Journal of Human Genetics

157

147

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Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%-25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 1003-20,0123) of five important mTOR pathway genes-PIK3CA, PIK3R2, AKT3, TSC1, and TSC2-by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.

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“…Public resources of human standing variation data continue to grow and have proven invaluable in modern-day interpretation of individual variants found among Mendelian disease genes, including the epilepsies ; Epi4K Consortium and Epilepsy Phenome/ Genome Project 2017; Kobayashi et al 2017;Walsh et al 2017). In this study, we take 11 dominant-acting epilepsy genes, seek subregions that are intolerant to missense variation and measure the concentration of pathogenic classified variants within these missense-intolerant regions.…”

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confidence: 99%

Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation

et al. 2017

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Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (P < 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney U test, P < 1 × 10

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Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

Cited by 577 publications

References 42 publications

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation

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