Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies

Purpose: The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.Methods: We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure.Results: Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among hot spot regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.Conclusions: Bayesian penetrance estimates provide a continuous framework for variant interpretation.(c) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Automated summary

This study applies a Bayesian penetrance estimation strategy to address the issue of incomplete penetrance in heterozygote carriers of genes KCNE1, KCNH2, and SCN5A associated with LQTS and BrS. Bayesian penetrance models were generated using variant-specific features and clinical data, and the posterior estimates were mapped onto protein structures. The results show that the penetrance of KCNE1 and SCN5A is equivalent to 10 and 5 clinically phenotype heterozygotes, respectively.