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Selecting variants of unknown significance through network-based gene-association significantly improves risk prediction for disease-control cohorts.

ABSTRACT: Variants of unknown/uncertain significance (VUS) pose a huge dilemma in current genetic variation screening methods and genetic counselling. Driven by methods of next generation sequencing (NGS) such as whole exome sequencing (WES), a plethora of VUS are being detected in research laboratories as well as in the health sector. Motivated by this overabundance of VUS, we propose a novel computational methodology, termed VariantClassifier (VarClass), which utilizes gene-association networks and polygenic risk prediction models to shed light into this grey area of genetic variation in association with disease. VarClass has been evaluated using numerous validation steps and proves to be very successful in assigning significance to VUS in association with specific diseases of interest. Notably, using VUS that are deemed significant by VarClass, we improved risk prediction accuracy in four large case-studies involving disease-control cohorts from GWAS as well as WES, when compared to traditional odds ratio analysis. Biological interpretation of selected high scoring VUS revealed interesting biological themes relevant to the diseases under investigation. VarClass is available as a standalone tool for large-scale data analyses, as well as a web-server with additional functionalities through a user-friendly graphical interface.

SUBMITTER: Oulas A

PROVIDER: S-EPMC6397233 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Selecting variants of unknown significance through network-based gene-association significantly improves risk prediction for disease-control cohorts.

Oulas Anastasis A Minadakis George G Zachariou Margarita M Spyrou George M GM

Scientific reports 20190301 1

Variants of unknown/uncertain significance (VUS) pose a huge dilemma in current genetic variation screening methods and genetic counselling. Driven by methods of next generation sequencing (NGS) such as whole exome sequencing (WES), a plethora of VUS are being detected in research laboratories as well as in the health sector. Motivated by this overabundance of VUS, we propose a novel computational methodology, termed VariantClassifier (VarClass), which utilizes gene-association networks and poly ...[more]

PMID: 30824863

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Project description:Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle metabolism characterized by generalized muscle rigidity, increased body temperature, rhabdomyolysis, hyperkalemia and severe metabolic acidosis. The underlying mechanism of MH involves excessive Ca2+ release from myotubes via the ryanodine receptor type 1 (RYR1) and the voltage-dependent L-type calcium channel (CACNA1S). As more than 300 variants of unknown significance have been detected to date, we examined whether freely available pathogenicity prediction tools are able to detect relevant MH causing variants. In this diagnostic accuracy study, blood samples from 235 individuals with a history of a clinical malignant hyperthermia or their close relatives were genetically screened for RYR1 variants of all 106 RYR1 exons and additionally for known variants of CACNA1S. In vitro contracture tests were conducted on muscle biopsies obtained from all individuals, independently of whether a pathogenic variant, a variant of unknown significance or no variant was detected. Comparisons were made to three established bioinformatic pathogenicity detection tools to identify the clinical impact of the variants of unknown significance. All detected genetic variants were tested for pathogenicity by three in silico approaches and compared to the in vitro contracture test. Sensitivity and specificity of exon screening of all individuals listed in our MH database was analyzed. Exon screening identified 97 (41%) of the 235 individuals as carriers of pathogenic variants. Variants of unknown significance were detected in 21 individuals. Variants of unknown significance were subdivided into 19 malignant-hyperthermia-susceptible individuals and 2 non-malignant-hyperthermia-susceptible individuals. All pathogenic variants as well as the malignant-hyperthermia-suspectible variants were correctly identified by the bioinformatic prediction tools. Sensitivity of in silico approaches ranged between 0.71 and 0.98 (Polyphen 0.94 [CI 95% 0.75; 0.99]; Sift 0.98 [CI 95% 0.81; 0.99]; MutationTaster 0.92 [CI 95% 0.75; 0.99]). Specificity differed depending on the used tool (Polphen 0.98 [CI 95% 0.32; 0.99]; Sift 0.98 [CI 95% 0.32; 0.99]; MutationTaster 0.00 [CI 95% 0.00; 0.60]). All pathogenic variants and variants of unknown significance were scored as probably damaging in individuals, demonstrating a high sensitivity. Specificity was very low in one of the three tested programs. However, due to potential genotype-phenotype discordance, bioinformatic prediction tools are currently of limited value in diagnosing pathogenicity of MH-susceptible variants.

Dataset Information

Selecting variants of unknown significance through network-based gene-association significantly improves risk prediction for disease-control cohorts.

Publications

Selecting variants of unknown significance through network-based gene-association significantly improves risk prediction for disease-control cohorts.

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