Titin mutation in familial restrictive cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Molecular Cardiology
• Genetic Basis of Heart Disease

Background:

• Familial restrictive cardiomyopathy (RCM) is a rare inherited heart muscle disease.
• Most known RCM-causing mutations are in sarcomere protein genes, also linked to hypertrophic cardiomyopathy (HCM).
• Previous RCM genetic causes include desmin and familial amyloidosis genes.

Purpose of the Study:

• To identify the genetic cause of familial restrictive cardiomyopathy in a family with severe heart failure.
• To investigate the role of titin (TTN) gene mutations in the pathogenesis of RCM.

Main Methods:

• Clinical evaluation including physical examination, ECG, and Doppler echocardiography.
• Genetic analysis involving linkage analysis to candidate loci and subsequent gene sequencing.
• Whole exome sequencing to exclude other cardiomyopathy-related gene mutations.

Main Results:

• Identified a de novo mutation (p.Y7621C) in exon 266 of the TTN gene in affected family members.
• The mutation affects a highly conserved fibronectin-3 domain in the A/I junction region of titin.
• No other pathogenic mutations were found in known cardiomyopathy genes.

Conclusions:

• This study demonstrates for the first time that TTN gene mutations can cause restrictive cardiomyopathy.
• Provides genetic evidence for titin's critical role in maintaining sarcomere resting tension and diastolic function.