In affected members of 2 families with hypertrophic cardiomyopathy mapping to the CMH3 locus on chromosome 15q2, Thierfelder et al. (1994) screened the candidate gene TPM1 and identified heterozygosity for 2 missense mutations, E180G (191010.0001) and D175N (191010.0002), ... In affected members of 2 families with hypertrophic cardiomyopathy mapping to the CMH3 locus on chromosome 15q2, Thierfelder et al. (1994) screened the candidate gene TPM1 and identified heterozygosity for 2 missense mutations, E180G (191010.0001) and D175N (191010.0002), respectively. Watkins et al. (1995) concluded that mutations in the TPM1 gene are a rare cause of CMH, accounting for approximately 3% of cases. These mutations, like those in the cardiac troponin T gene (TNNT2; 191045) that cause CMH2 (115195), are characterized by relatively mild and sometimes subclinical hypertrophy but a high incidence of sudden death. Genetic testing may therefore be especially important in this group. In a large Spanish American family with multiple members affected with hypertrophic cardiomyopathy, Karibe et al. (2001) identified a heterozygous missense mutation in the TPM1 gene (V95A; 191010.0003) that segregated with disease. The authors noted that this mutation was associated with the same mild degree of left ventricular hypertrophy as seen in some CMH1 families harboring specific mutations in MYH7 (160760.0010, 160760.0012, 160760.0001). Penetrance was estimated at 53% on the basis of an abnormal echocardiogram; however, 2 mutation carriers with normal echocardiograms and normal ECGs were only in their mid-thirties at the time of the study. Penetrance could not be accurately assessed by ECG, since 6 older mutation-negative family members had minor T-wave changes. Cumulative survival rates in this family were 73% +/- 10% at 40 years and 32% +/- 13% at 60 years. In a 36-year-old woman of Italian extraction with cardiomyopathy, in whom a transthoracic echocardiogram was consistent with a restrictive phenotype (RCM), Caleshu et al. (2011) sequenced the exons and exon-intron boundaries of 8 known cardiomyopathy-associated genes and identified homozygosity for a missense mutation (N279H) in the TPM1 gene. The patient's cardiac catheterization pattern was consistent with a restrictive phenotype, although the dip-plateau ('square-root sign') was absent. Her first-cousin parents were each heterozygous for the mutation. Her affected 75-year-old father had been diagnosed with hypertrophic cardiomyopathy at 42 years of age, and had a history of heart failure but was currently asymptomatic. His most recent echocardiogram showed moderate asymmetric hypertrophy, mild pulmonary hypertension, mild left ventricular systolic dysfunction, and moderate biatrial enlargement, suggesting a chronic restrictive physiology. The asymptomatic 67-year-old mother underwent echocardiography after her daughter's diagnosis that revealed septal and posterior wall thicknesses that were at the upper limit of normal, with mild biatrial enlargement with normal systolic function and no significant evidence of restrictive physiology.