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Expanding the phenotype of biallelic variants in the MYBPC3 gene: sudden death in a teenager with a structurally normal heart.

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Monoallelic pathogenic variant in the MYBPC3 gene are responsible for about 50% of autosomal dominant adult-onset hypertrophic cardiomyopathy and 2% of dilated cardiomyopathy cases. By contrast, biallelic pathogenic variants in this gene are considered rare and associated with a severe early onset cardiac phenotype, characterized by poor prognosis and an increased frequency of heart failure and sudden cardiac death. There are less than 30 cases reported in the literature of pediatric patients harboring biallelic pathogenic variants in the MYBPC3 gene, and they were all found to have either hypertrophic cardiomyopathy or left ventricular noncompaction.

Case Presentation
Here, we present on a 14-year-old female of Pakistani ancestry who suffered a sudden cardiac arrest. Serial echocardiograms revealed a structurally normal heart with only a mild hypertrabeculated appearance of the left ventricle. Despite a prompt resuscitation attempt, she eventually passed 8 days after the initial presentation from bradycardic cardiac arrest. Family history was significant for consanguinity, with parents reportedly being first cousins, a full sister who passed at 9 months of age from cardiorespiratory arrest, and a healthy older full sister.

Diagnostic Workup
Rapid trio whole genome sequencing identified a homozygous intronic pathogenic variant in the MYBPC3 gene (c.1224-52 G>A). Each parent and the surviving older sister were confirmed to harbor the same variant in the heterozygous state. Additionally, there was a de novo variant of uncertain significance identified in the TRPM4 gene (c.326 A>C; p.Asp79Ala), predicted by in silico analysis not to alter protein structure and function; monoallelic pathogenic variants in this gene are associated with familial heart block type IB and Brugada syndrome.

Discussion
The c.1224-52 G>A variant identified in our patient is one of the most frequently reported pathogenic variant in the heterozygous state across all adult-onset hypertrophic cardiomyopathy genes, and it is thought to be a highly penetrant allele. By contrast, there is only one report in the literature of a 2-year-old female and her infant brother who harbored the c.1224-52 G>A variant in the homozygous state; they both had hypertrophic cardiomyopathy, with the sister presenting also biventricular heart failure. 

Conclusion
This is the first time biallelic variants are reported in a patient with a structurally normal heart who presented with sudden death. This case expands on the phenotype of biallelic variants in the MYBPC3 gene; it also highlights the importance of looking for secondary variants in this gene in pediatric patients with normal echocardiographic findings, as it could impact long term management and survival.

Agenda

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