Exploring the utility of whole-exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness


  • J. R. L. is a consultant for Athena Diagnostics, has stock ownership in 23andMe and Ion Torrent Systems, and is a co-inventor on multiple United States and European patents for DNA diagnostics. R. A. G. was a founding shareholder in Seq-Wright, Inc. Some of the authors are based in the Department of Molecular and Human Genetics at Baylor College of Medicine, which derives revenue from genetic laboratory testing, including whole-exome sequencing. The remaining authors have no conflicts of interest to declare.

Corresponding author: Chester W. Brown, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Tel.: 713-798-3994

fax: 713-798-7418

e-mail: cbrown@bcm.edu


The advent of whole-exome next-generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½-year old female patient with a 2-year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work-up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di-deoxy sequencing. WES revealed a de novo non-synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.