RT Journal Article
SR Electronic
T1 Predicting Functional Effects of Missense Variants in Voltage-Gated Sodium and Calcium Channels
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 671453
DO 10.1101/671453
A1 Henrike O. Heyne
A1 David Baez-Nieto
A1 Sumaiya Iqbal
A1 Duncan Palmer
A1 Andreas Brunklaus
A1 the Epi25 Collaborative
A1 Katrine M. Johannesen
A1 Stephan Lauxmann
A1 Johannes R. Lemke
A1 Rikke S. Møller
A1 Eduardo Pérez-Palma
A1 Ute Scholl
A1 Steffen Syrbe
A1 Holger Lerche
A1 Patrick May
A1 Dennis Lal
A1 Arthur J. Campbell
A1 Jen Pan
A1 Hao-Ran Wang
A1 Mark J. Daly
YR 2019
UL http://biorxiv.org/content/early/2019/06/14/671453.abstract
AB 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.