Investigating TNNC1 gene inheritance and clinical outcomes through a comprehensive familial study

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Disease Mechanisms

Background:

• Hypertrophic cardiomyopathy (HCM) and restrictive cardiomyopathy (RCM) share genetic and phenotypic similarities, primarily linked to sarcomeric gene variants.
• HCM is common, whereas RCM is rare, often underdiagnosed, and carries a poor prognosis.

Purpose of the Study:

• To investigate the genetic basis of fatal restrictive cardiomyopathy in a family with affected infants.
• To explore the phenotypic spectrum of a specific sarcomeric variant in hypertrophic and restrictive cardiomyopathy.

Main Methods:

• Family-based genetic analysis.
• Genotyping of affected infants and relatives for the TNNC1 variant.
• Clinical phenotyping including echocardiography.

Main Results:

• Four infants presented with fatal RCM and biventricular hypertrophy, all homozygous for the TNNC1:c.23C>T(p.Ala8Val) variant.
• Heterozygous carriers in the family exhibited a mild form of HCM with low penetrance.
• The study highlights variable expressivity and incomplete penetrance of the TNNC1 variant.

Conclusions:

• The TNNC1:c.23C>T(p.Ala8Val) variant demonstrates distinct inheritance patterns leading to severe RCM in homozygotes and milder HCM in heterozygotes.
• Genetic testing is crucial for diagnosing cardiomyopathies, predicting prognosis, and guiding early interventions.
• Understanding genotype-phenotype correlations is vital for managing inherited heart conditions.