D117N in Cypher/ZASP may not be a causative mutation for dilated cardiomyopathy and ventricular arrhythmias

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Disease Etiology

Background:

• Dilated cardiomyopathy (DCM) and ventricular arrhythmias are significant causes of heart failure and sudden death in young individuals.
• The cytoskeletal protein Cypher/ZASP, located at the sarcomeric Z-line, is crucial for cardiac structure and function.
• A specific Cypher/ZASP variant, p.(D117N), was previously hypothesized to cause cardiac dysfunction based on limited case reports.

Purpose of the Study:

• To investigate the role of the Cypher/ZASP p.(D117N) variant in two unrelated Bedouin families with pediatric DCM and early-onset DCM with ventricular arrhythmias.
• To determine if p.(D117N) is the causative mutation for these cardiac conditions in the studied families.

Main Methods:

• Whole exome sequencing was employed to identify genetic variants in affected family members.
• Segregation analysis was performed to assess the co-occurrence of the p.(D117N) variant with the disease phenotype within families.
• Carrier frequency of the p.(D117N) variant was determined in the relevant Bedouin population.

Main Results:

• The p.(D117N) variant in Cypher/ZASP was identified in the affected families but did not segregate with the disease.
• The variant was present in unaffected individuals and absent in some affected patients, refuting its causative role.
• A carrier frequency of 5.2% for p.(D117N) was observed in the Bedouin population, significantly exceeding the incidence of idiopathic DCM.

Conclusions:

• The p.(D117N) variant in Cypher/ZASP is not the causative mutation for DCM or ventricular arrhythmias in the investigated Bedouin families.
• The high population frequency of this variant suggests it is likely benign or has a complex, non-causative role in cardiac pathologies.
• Further research is required to clarify the precise function of the D117N variant in Cypher/ZASP and its potential contribution to cardiac disease.