Identification of the mutation MYBPC3:Tyr333Ter in multiple Arab families in East Jerusalem

Introduction: The MYBPC3 gene encodes the cardiac myosin-binding-protein-C which composites the sarcomere in the myocytes. Mutations in this gene are a common cause of familial hypertrophic cardiomyopathy (HCM), accounting for up to 30-40% of all cases. Affected individuals have an increased risk for heart failure and sudden cardiac death (SCD) compared to other causes of cardiomyopathy. Recent guidelines recommend genetic testing in affected patients. Since the disease is inherited in an autosomal dominant pattern, cascade genetic testing of relatives of carriers can facilitate early diagnosis, treatment and prevention. Lately, novel therapeutic strategies to mutated MYBPC3 patients are being tested. Variants in this gene have been associated with other cardiomyopathies such as left ventricular noncompaction, dilated, and restrictive cardiomyopathy.

Materials and methods: Genetic counseling, evaluation and screening are done to cardiomyopathy patients referred to the Cardio-Genetic Unit at Hadassah Hebrew University Medical Center, Jerusalem. Genetic data is obtained using next-generation-sequencing techniques and specifically designed gene panels. In specific cases, whole-exome-sequencing (WES) is applied.

Results and discussion: Using Sanger sequencing, cardiomyopathy genes panel, and WES, we found three allegedly unrelated Arab families carrying the truncating mutation in MYBPC3 gene: c.999C>A (p.Tyr333Ter). In each family, there are several affected individuals. Searching Hadassah`s Exome results` database revealed two other families in which this variant was accidently found. Interestingly, the only description of this variant in international public domains, originates from Egypt.

Conclusion: We have identified five Arab families living in east Jerusalem carrying the Tyr333Ter mutation. This mutation is relatively widespread among Arab families in the area, possibly due to an ancient founder mutation. We are currently conducting a research to further define the prevalence and origin of this mutation.