Journal article

Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation

Joshua Traynelis, Michael Silk, Quanli Wang, Samuel F Berkovic, Liping Liu, David B Ascher, David J Balding, Slave Petrovski

GENOME RESEARCH | COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT | Published : 2017

Abstract

Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address..

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Grants

Awarded by National Health and Medical Research Council (NHMRC)


Awarded by Jack Brockhoff Foundation


Awarded by NHMRC


Funding Acknowledgements

We thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. We also thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison; a full list of contributing groups can be found at http://exac.broadinstitute.org/about. D.B.A. was supported by a National Health and Medical Research Council (NHMRC) C.J. Martin Research Fellowship (APP1072476) and the Jack Brockhoff Foundation (JBF 4186, 2016). S.P. was supported by an NHMRC R.D. Wright Career Development Fellowship (1126877).