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Sci Transl Med DOI:10.1126/scitranslmed.aay6848

Predicting functional effects of missense variants in voltage-gated sodium and calcium channels.

Publication TypeJournal Article
Year of Publication2020
AuthorsHeyne, HO, Baez-Nieto, D, Iqbal, S, Palmer, DS, Brunklaus, A, May, P, Johannesen, KM, Lauxmann, S, Lemke, JR, Møller, RS, Pérez-Palma, E, Scholl, UI, Syrbe, S, Lerche, H, Lal, D, Campbell, AJ, Wang, H-R, Pan, J, Daly, MJ
Corporate AuthorsEpi25 Collaborative
JournalSci Transl Med
Volume12
Issue556
Date Published2020 08 12
ISSN1946-6242
KeywordsCalcium Channels, Mutation, Missense, Pharmaceutical Preparations, Phenotype, Sodium
Abstract

Malfunctions of voltage-gated sodium and calcium channels (encoded by and family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF ( = 518) and GOF ( = 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects [area under the receiver operating characteristics curve (ROC) = 0.85] of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in and (ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the family genes.

DOI10.1126/scitranslmed.aay6848
Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/32801145?dopt=Abstract

Alternate JournalSci Transl Med
PubMed ID32801145