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Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels
Heyne, Henrike O.; Baez-Nieto, David; Iqbal, Sumaiya et al.


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Keywords :
Voltage-gated ion channels; GOF/LOF; Variant classification
Abstract :
[en] Malfunctions of voltage-gated sodium and calcium channels (SCN and CACNA1 genes) 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) which is not only corresponding 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. Based on known gene-disease-mechanisms, we here infer LOF (518 variants) and GOF (309 variants) of likely pathogenic variants from disease phenotypes of variant carriers. We show regional clustering of inferred GOF and LOF variants, respectively, across the alignment of the entire gene family, suggesting shared pathomechanisms in the SCN/CACNA1 genes. By training a machine learning model on sequence- and structure-based features we predict LOF- or GOF- associated disease phenotypes (ROC = 0.85) of likely pathogenic missense variants. We then successfully validate the GOF versus LOF prediction on 87 functionally tested variants in SCN1/2/8A and CACNA1I (ROC = 0.73) and in exome-wide data from > 100.000 cases and controls. Ultimately, functional prediction of missense variants in clinically relevant genes will facilitate precision medicine in clinical practice.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Heyne, Henrike O.
Baez-Nieto, David
Iqbal, Sumaiya
Palmer, Duncan
Brunklaus, Andreas
Johannesen, Katrine M.
Lauxmann, Stephan
Lemke, Johannes R.
Møller, Rikke S.
Pérez-Palma, Eduardo
Scholl, Ute
Syrbe, Steffen
Lerche, Holger
MAY, Patrick  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Lal, Dennis
Campbell, Arthur J.
Pan, Jen
Wang, Hao-Ran
Daly, Mark J.
More authors (10 more) Less
Language :
Title :
Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels
Publication date :
Focus Area :
Systems Biomedicine
Available on ORBilu :
since 07 July 2019


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