Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin

Background: TTN-encoded titin, CSRP3-encoded muscle LIM protein, and TCAP-encoded telethonin are Z-disc proteins essential for the structural organization of the cardiac sarcomere and the cardiomyocyte's stretch sensor. All three genes have been established as cardiomyopathy-associated genes for both dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Here, we sought to characterize the frequency, spectrum, and phenotype associated with HCM-associated mutations in these three genes in a large cohort of unrelated patients evaluated at a single tertiary outpatient center. Methods: DNA was obtained from 389 patients with HCM (215 male, left ventricular wall thickness of 21.6 ± 6 mm) and analyzed for mutations involving all translated exons of CSRP3 and TCAP and targeted HCM-associated exons (2, 3, 4, and 14) of TTN using polymerase chain reaction (PCR), denaturing high performance liquid chromatography (DHPLC), and direct DNA sequencing. Clinical data were extracted from patient records and maintained independent of the genotype. Results: Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP mutation and 4 patients a TCAP mutation. No TTN mutations were detected. Seven patients were also found to have a concomitant myofilament mutation. Seven patients with a MLP-mutation were found to harbor the DCM-associated, functionally characterized W4R mutation. W4R-MLP was also noted in a single white control subject. Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM. Conclusions: Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations. MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation. The precise role of W4R-MLP in the pathogenesis of either DCM or HCM warrants further investigation.