KBTBD13 is a novel cardiomyopathy gene

Area of Science:

• Genetics
• Cardiology
• Neuromuscular Disorders

Background:

• KBTBD13 variants are known to cause nemaline myopathy type 6 (NEM6).
• The Dutch founder variant, KBTBD13 p.R408C, is prevalent in NEM6 patients.
• KBTBD13 expression in cardiac muscle suggests potential cardiac involvement, which remains largely unknown in NEM6.

Purpose of the Study:

• To investigate cardiac involvement in patients with NEM6 carrying the KBTBD13 p.R408C variant.
• To determine the association between KBTBD13 variants and cardiac dysfunction.
• To evaluate the need for cardiac screening in NEM6 patients.

Main Methods:

• Pedigree construction and clinical evaluation of three families with the KBTBD13 p.R408C variant.
• Assessment of cardiac function, including left ventricle dimensions, ejection fraction, and electrophysiological parameters in 65 patients.
• Linkage analysis to confirm cosegregation of the KBTBD13 p.R408C variant with cardiac phenotypes.
• Phenotypic analysis in Kbtbd13 variant and deficient mouse models.

Main Results:

• In evaluated patients, significant cardiac abnormalities were observed: 12% left ventricle dilatation, 29% reduced ejection fraction (<50%), 8% atrial fibrillation, 9% ventricular tachycardia, and 20% repolarization abnormalities.
• Five patients required implantable cardioverter defibrillators, and three cases of sudden cardiac death were reported.
• Mouse studies indicated diastolic dysfunction in Kbtbd13 p.R408C variant mice and systolic dysfunction in Kbtbd13-deficient mice.

Conclusions:

• KBTBD13 is associated with cardiac dysfunction and cardiomyopathy.
• KBTBD13 should be included in genetic testing panels for cardiomyopathy.
• Nemaline myopathy type 6 patients with KBTBD13 variants require cardiological referral and monitoring.