Familial dilated cardiomyopathy is a major cause of advanced
heart failure and
heart transplantation. In most families, the disease-causing mutation is unknown, and relatives should therefore undergo periodic screening to facilitate early diagnosis and
therapy. In the present study, we describe a novel
titin truncation mutation causing adult-onset
familial dilated cardiomyopathy in an Israeli Arab family. The family members underwent physical examination, electrocardiography, and Doppler echocardiography. Linkage to candidate loci was performed, followed by gene sequencing. We identified 13 clinically affected family members (8 men and 5 women, mean age 47 ± 12 years). Compared with their healthy first-degree relatives, the affected relatives had a larger end-diastolic left ventricular dimension (60 ± 10 vs 49 ± 4 mm, p <0.001), lower ejection fraction (43 ± 11% vs 60 ± 6%, p <0.001), and markedly higher end-systolic volume indexes but no difference in wall thickness or diastolic function. The linkage studies or direct sequencing excluded LMNA, MYH7, TNNT2, TNNI3, SCN5A, DES, SGCD, ACTC, PLN, and MYH6 but established linkage to the TTN locus at chromosome 2q31, yielding a maximum (2-point) LOD score of 3.44. Sequence analysis identified an insertion (c.58880insA), causing
protein truncation after 19,628
amino acids (p.S19628IfsX1). No founder effect was found among the Israeli Arabs. In conclusion,
titin is a giant
protein with a key role in sarcomere assembly, force transmission, and maintenance of resting tension. Although some mutations result in skeletal
myopathy, others cause isolated, maturity-onset
cardiomyopathy.