Biology subjects

Thomson, K. L.

Publications and source records attributed to Thomson, K. L..

3 recordsLinked to original sources

bioRxiv2021

A calibrated functional patch clamp assay to enhance clinical variant interpretation in KCNH2-related long QT syndrome

PurposeModern sequencing technologies have revolutionised our detection of gene variants. In most genes, including KCNH2, the majority of missense variants are currently classified as variants of uncertain significance (VUS). The aim of this study is to investigate the utility of an automated patch-clamp assay for aiding clinical variant classification in the KCNH2 gene. MethodsThe assay was designed according to recommendations of the ClinGen sequence variant interpretation framework. Thirty-one control variants of known clinical significance (17 pathogenic/likely pathogenic, 14 benign/likely benign) were heterozygously expressed in Flp-In HEK293 cells. Variants were analysed for effects on current density and channel gating. A panel of 44 VUS was then assessed for reclassification. ResultsAll 17 pathogenic variant controls had reduced current density and 13/14 benign variant controls had normal current density, which enabled determination of normal and abnormal ranges for applying moderate or supporting evidence strength for variant classification. Inclusion of KCNH2 functional assay evidence enabled us to reclassify 6 out of 44 VUS as likely pathogenic. ConclusionThe high-throughput patch clamp assay can provide moderate strength evidence for clinical interpretation of clinical KCNH2 variants and demonstrates the value proposition for developing automated patch clamp assays for other ion channel genes.

genetics↗

bioRxiv2018

Response to Shah et al: Using high-resolution variant frequencies empowers clinical genome interpretation and enables investigation of genetic architecture

Main text Main text Supplemental Data description Declaration of Interests Web Resources References Recent work by Shah and colleagues1 demonstrated that many variants in the ClinVar database2 are misclassified, and that disease-specific allele frequency (AF) thresholds can identify wrongly classified alleles by flagging variants that are too prevalent in the population to be causative of rare penetrant disease. While we agree with the main conclusions of this work, the authors compare their AF filtering approach to our recently published method3, concluding that the method we advanced \"may be prone to removing potentially pathogenic variants\". This is incorrect. Here we demonstrate that our approach is robust, and further illustrate the power of di ...

genomics↗

bioRxiv2018

Quantitative approaches to variant classification increase the yield and precision of genetic testing in Mendelian diseases: The case of hypertrophic cardiomyopathy

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.\n\nResultsWe compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). Analysis 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, and therefore clinically actionable, were identified in 5 established HCM genes. Applying this approach leads to an estimated 14-20% increase in cases with actionable HCM variants.\n\nConclusionsWhen 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, unbiased and equitable 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.

genetics↗