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

Figures

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  Visual Summary. Genotype-Phenotype Discordance in FKRP Cardiomyopathy Two siblings homozygous for FKRP c.1100T>C developed divergent cardiac phenotypes despite identical genotype. Patient 1 (male, age 25) developed dilated cardiomyopathy with fibrosis involving 12 to 14 of 17 AHA segments despite partial LVEF recovery on guideline-directed therapy (EF: 41%→43%). Patient 2 (female, age 30) had nondilated cardiomyopathy with stable, limited fibrosis (4/17 AHA segments) and preserved function (EF: 50%→59%). The key finding was dissociation between ejection fraction improvement and fibrosis progression, demonstrating that EF alone underestimates disease activity. AHA = American Heart Association; CMR = cardiac magnetic resonance; EF = ejection fraction; LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction.

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  Figure 1. Left Ventricular Ejection Fraction Over Time Left ventricular ejection fraction plotted by patient age from echocardiography (Echo; open circles and dashed lines) and cardiac magnetic resonance (CMR; filled circles and solid lines). The dashed gray reference lines indicate severity thresholds: normal (≥53%), mildly reduced (41%-52%), and moderately reduced (30%-40%). Patient 1 (teal) demonstrated fluctuating ejection fraction with echocardiographic values generally lower than CMR-derived measurements. Patient 2 (rose) showed gradual decline from normal to mildly reduced function across both imaging modalities. GDMT = guideline-directed medical therapy.

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  Figure 2. Temporal Progression of Myocardial Fibrosis on AHA 17-Segment Late Gadolinium Enhancement Maps Sequential AHA 17-segment bull's-eye maps; color intensity indicates LGE severity (none, subtle, moderate, extensive). Left ventricular ejection fraction (EF) and end-diastolic volume index (EDVi) are annotated below each time point. Patient 1 demonstrated fibrosis involving 12 to 14 segments over 7 years, coinciding with transition from nondilated (EDVi: 99 mL/m2) to dilated cardiomyopathy (EDVi: 129 mL/m2), followed by partial reverse remodeling (EDVi: 104 mL/m2) despite continued fibrosis progression. Patient 2 showed stable fibrosis confined to 4 lateral segments, with normal volumes. AHA = American Heart Association; LGE = late gadolinium enhancement.

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  Figure 3. Most Recent AHA 17-Segment Late Gadolinium Enhancement Maps LGE distribution mapped to the AHA 17-segment bull's-eye model at the most recent CMR; color intensity indicates LGE severity (none, subtle, moderate, extensive). Patient 1 demonstrated extensive fibrosis involving 14 of 17 segments a mid-wall and subepicardial distribution. Patient 2 shows focal subepicardial enhancement confined to 4 lateral segments. Segment key table at the bottom provides per-segment comparison. AHA = American Heart Association; CMR = cardiac magnetic resonance; LGE = late gadolinium enhancement.

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  Figure 4. Genotype-Phenotype Discordance in FKRP-Related Cardiomyopathy Conceptual diagram illustrating how a single homozygous FKRP c.1100T>C genotype produces divergent cardiac phenotypes through the interplay of sex, modifier genes, and environmental factors. Patient 1 (male, age 25, skeletal onset by age 6 months, loss of ambulation at age 23) developed dilated cardiomyopathy with progressive fibrosis; patient 2 (female, age 30, skeletal onset age ∼1 year, loss of ambulation at age 27) had nondilated cardiomyopathy with stable focal fibrosis. Because limb-girdle muscular dystrophy R9 is autosomal recessive, siblings should undergo cascade genetic testing, with cardiac surveillance initiated for those carrying biallelic pathogenic variants. Serial CMR with LGE quantification is needed regardless of ejection fraction trajectory. CMR = cardiac magnetic resonance; EDVi = end-diastolic volume index; LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction.