Mosaic RYR2 mutation identified in a childhood-onset cardiac disorder

Sarah Pantaleo*, Belinda Chong1, Daniel Flanagan1, Ivan Macciocca 2, Jacob Mathew 3 & Desirée du Sart1

1 Molecular Genetics Laboratory, Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Victoria, Australia
2 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Victoria, Australia
3 Cardiology Department, Royal Children’s Hospital, Victoria, Australia


We use a custom Next Generation Sequencing gene panel to screen patients with cardiomyopathies, arrhythmias, aortopathies and congenital heart disease.  Data analysis occurs through a custom pipeline and the complete coding sequences of all genes are screened and all variants with population database frequency <1% are reported.

A 12 y.o. boy presented with dilated cardiomyopathy [DCM], multiple arrhythmias and cardiac remodelling.  We analysed variants in genes associated with cardiomyopathies and arrhythmias in this patient and identified a novel, potentially disease-causing variant in the RYR2 gene.  This variant was predicted to be deleterious by in silico software programs, was not present in a population database and was not reported previously in any cardiac disorder cases. It was classified as a variant of uncertain significance with high clinical significance. Upon analysing the NGS data, it was apparent that the variant was mosaic at a level of 22% (mutant allele present in 114/391 reads) and this was also evident on the Sanger sequencing confirmation performed on the blood DNA.

There are many genes associated with DCM, representing marked locus heterogeneity.  The RYR2 gene is not reported to be associated with pure DCM however, it is reported to be associated with CPVT, a condition characterized by an abnormal heart rhythm and ARVD, a disorder of the muscular wall of the heart. The significance of this mosaic finding in blood DNA is uncertain. Data from further analyses will be presented to help clarify whether this variant is disease-causing, such as parental testing to confirm whether it is de novo and testing of other tissues from the patient, in particular cardiac muscle to detect the level of mosaicism present.

This case highlights the complexity of identifying a genetic cause in cardiac cases which have complex etiology.


Daniel Flanagan is a Medical Scientist at the Victorian Clinical Genetics Services (VCGS) with over 6 years of experience in molecular genetics.  His main focus at the VCGS is the testing and classification of genetics variants associated with cardiac disorders, and the development of tests for rare disorders.  He also has experience and a keen interest in developing automation protocols for molecular techniques.

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