Abstract
BackgroundInternational guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework.MethodsWe compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases.ResultsAnalysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14–20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands’ relatives.ConclusionsWhen found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a “likely pathogenic” classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent and unbiased approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.
Highlights
International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield
We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner
Using etiological fraction (EF) to increase the yield of putatively pathogenic variants in hypertrophic cardiomyopathy (HCM) cohorts Sarcomeric gene rare variants in the Oxford Molecular Genetics Laboratory (OMGL)/Laboratory of Molecular Medicine (LMM) clinical cohort [3] were re-assessed based on the analysis described above
Summary
International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test sensitivity and diagnostic yield. In an effort to standardise variant assessment in clinical settings, guidelines from the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) were produced in 2015 [1] and have been widely adopted [2] These were in part prompted by the plethora of erroneous variant-disease associations in the research literature [3, 4] and the increasing realisation that individually rare variants are collectively common for many genes, as highlighted by population datasets such as the Exome Aggregation Consortium (ExAC) [5]. The ACMG/AMP guidelines outline how different lines of evidence should be assessed when interpreting a variant, and the strength of evidence required for a pathogenic (or likely pathogenic) classification They are deliberately broad in scope, with the intention that individual rules would be interpreted and adapted for specific diseases within the overall framework [6]. While novel truncating variants can be classified as pathogenic (when found in a gene where loss of function is a known mechanism of disease and fulfilling other conditions such as rarity), variant-specific evidence (such as segregation in the family or prior functional evidence of pathogenicity) is required for non-truncating variants to be reported as pathogenic
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