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Exploiting ion channel structure to assess rare variant pathogenicity.

ABSTRACT: BACKGROUND:A 27-year-old woman was seen for long QT syndrome. She was found to be a carrier of 2 variants, KCNQ1 Val162Met and KCNH2 Ser55Leu, and both were classified as "pathogenic" by a diagnostic laboratory, in part because of sequence proximity to other known pathogenic variants. OBJECTIVE:The purpose of this study was to assess the relationship between both the KCNQ1 and KCNH2 variants and clinical significance using protein structure, in vitro functional assays, and familial segregation. METHODS:We used co-segregation analysis of family, patch clamp in vitro electrophysiology, and structural analysis using recently released cryo-electron microscopy structures of both channels. RESULTS:The structural analysis indicates that KCNQ1 Val162Met is oriented away from functionally important regions while Ser55Leu is positioned at domains critical for KCNH2 fast inactivation. Clinical phenotyping and electrophysiology study further support the conclusion that KCNH2 Ser55Leu is correctly classified as pathogenic but KCNQ1 Val162Met is benign. CONCLUSION:Proximity in sequence space does not always translate accurately to proximity in 3-dimensional space. Emerging structural methods will add value to pathogenicity prediction.

SUBMITTER: Kroncke BM

PROVIDER: S-EPMC5984725 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Exploiting ion channel structure to assess rare variant pathogenicity.

Kroncke Brett M BM Yang Tao T Kannankeril Prince P Shoemaker M Benjamin MB Roden Dan M DM

Heart rhythm 20180109 6

<h4>Background</h4>A 27-year-old woman was seen for long QT syndrome. She was found to be a carrier of 2 variants, KCNQ1 Val162Met and KCNH2 Ser55Leu, and both were classified as "pathogenic" by a diagnostic laboratory, in part because of sequence proximity to other known pathogenic variants.<h4>Objective</h4>The purpose of this study was to assess the relationship between both the KCNQ1 and KCNH2 variants and clinical significance using protein structure, in vitro functional assays, and familia ...[more]

PMID: 29330128

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Project description:Clinically identified genetic variants in ion channels can be benign or cause disease by increasing or decreasing the protein function. As a consequence, therapeutic decision-making is challenging without molecular testing of each variant. Our biophysical knowledge of ion-channel structures and function is just emerging, and it is currently not well understood which amino acid residues cause disease when mutated. We sought to systematically identify biological properties associated with variant pathogenicity across all major voltage and ligand-gated ion-channel families. We collected and curated 3049 pathogenic variants from hundreds of neurodevelopmental and other disorders and 12 546 population variants for 30 ion channel or channel subunits for which a high-quality protein structure was available. Using a wide range of bioinformatics approaches, we computed 163 structural features and tested them for pathogenic variant enrichment. We developed a novel 3D spatial distance scoring approach that enables comparisons of pathogenic and population variant distribution across protein structures. We discovered and independently replicated that several pore residue properties and proximity to the pore axis were most significantly enriched for pathogenic variants compared to population variants. Using our 3D scoring approach, we showed that the strongest pathogenic variant enrichment was observed for pore-lining residues and alpha-helix residues within 5Å distance from the pore axis centre and not involved in gating. Within the subset of residues located at the pore, the hydrophobicity of the pore was the feature most strongly associated with variant pathogenicity. We also found an association between the identified properties and both clinical phenotypes and functional in vitro assays for voltage-gated sodium channels (SCN1A, SCN2A, SCN8A) and N-methyl-D-aspartate receptor (GRIN1, GRIN2A, GRIN2B) encoding genes. In an independent expert-curated dataset of 1422 neurodevelopmental disorder pathogenic patient variants and 679 electrophysiological experiments, we show that pore axis distance is associated with seizure age of onset and cognitive performance as well as differential gain versus loss-of-channel function. In summary, we identified biological properties associated with ion-channel malfunction and show that these are correlated with in vitro functional readouts and clinical phenotypes in patients with neurodevelopmental disorders. Our results suggest that clinical decision support algorithms that predict variant pathogenicity and function are feasible in the future.

Dataset Information

Exploiting ion channel structure to assess rare variant pathogenicity.

Publications

Exploiting ion channel structure to assess rare variant pathogenicity.

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