Discordant Cardiomyopathy Phenotypes in Siblings With Homozygous FKRP c.1100T>C

Pathogenic FKRP variants cause limb-girdle muscular dystrophy R9, with variable cardiac involvement. How genotype influences the cardiac phenotype remains poorly defined for non-European founder variants.

We report 2 siblings of South African Afrikaner descent, both homozygous for FKRP c.1100T>C (p.Ile367Thr), with discordant cardiac phenotypes. The brother (age 25 years) presented at age 17 with nondilated cardiomyopathy (left ventricular ejection fraction [LVEF]: 41%) that progressed to dilated cardiomyopathy, with fibrosis involving 12 to 14 of 17 AHA (American Heart Association) segments late gadolinium enhancement segments over 7 years despite partial reverse remodeling. His sister (age 30 years) had nondilated cardiomyopathy with preserved LVEF (59%) and stable fibrosis in 4 lateral segments over 2 years.

Serial cardiac magnetic resonance revealed dissociation between functional recovery and fibrosis progression: LVEF improved on guideline-directed therapy, while fibrosis burden remained extensive.

Ejection fraction alone underestimates disease progression in FKRP-related cardiomyopathy. Serial cardiac magnetic resonance with late gadolinium enhancement should guide surveillance, especially in non-c.826C>A genotypes where cardiac onset occurs decades earlier.