Cardiomyopathy, Familial Hypertrophic, 18

A number sign (#) is used with this entry because of evidence that hypertrophic cardiomyopathy can be caused by heterozygous mutation in the gene encoding phospholamban (PLN; 172405) on chromosome 6q22.1.

For a phenotypic description and a discussion of genetic heterogeneity of familial hypertrophic cardiomyopathy, see CMH1 (192600).

Clinical Features

Minamisawa et al. (2003) studied a 2-generation family with hypertrophic cardiomyopathy (CMH) in which the female proband presented at 56 years of age with paroxysmal atrial fibrillation and was found to have left ventricular hypertrophy on electrocardiogram. Echocardiography showed that the thicknesses of the septum and posterior wall of the left ventricle were 30 mm and 13 mm, respectively. The diastolic and systolic dimensions of the left ventricle were 48 mm and 27 mm, respectively. The proband's family history was consistent with a late-onset type of CMH: her father, who had been diagnosed with cardiomyopathy, died at 82 years of age, and an older brother was also diagnosed with CMH at age 62 years.

Medin et al. (2007) studied a family in which the 85-year-old female proband was diagnosed with apical CMH at 67 years of age, with a maximum wall thickness of 22 mm at the apex and normal thickness in basal segments. She originally presented with palpitations and chest pain at 59 years of age but had normal coronary angiography; she developed atrial fibrillation 2 years later, and continued to have occasional episodes of angina. Her brother was diagnosed with apical CMH at 72 years of age after presenting with palpitations, remained in atrial fibrillation after diagnosis, had atypical chest pain, and died suddenly at 81 years of age. Screening of the proband's 3 asymptomatic sons revealed that 1 had apical CMH with mild hypertrophy at age 59 years; the other 2 had normal electro- and echocardiograms.

Chiu et al. (2007) reported a 65-year-old Australian woman who was diagnosed with CMH at age 61 years, in whom echocardiography revealed asymmetric septal hypertrophy with a maximum wall thickness of 20 mm, normal systolic contractile function, and no evidence of left ventricular dilation. She had recurrent atrial fibrillation, palpitations, dyspnea, and presyncope. Her mother had also been diagnosed with CMH and had died at age 80 years of noncardiac causes.

Landstrom et al. (2011) described a 4-generation family with CMH, in which the 58-year-old male proband presented with palpitations at age 51 years and was diagnosed with CMH. Over the next 2 years, he had recurrent palpitations and chest pain with normal angiography, and was diagnosed with Wolff-Parkinson-White preexcitation syndrome (WPW; see 194200). He eventually underwent placement of an internal cardioverter-defibrillator for symptomatic nonsustained ventricular tachycardia. The proband's deceased mother also had CMH, and a granddaughter, whose mother had no signs of CMH, was diagnosed with CMH by echocardiography.

Molecular Genetics

Minamisawa et al. (2003) analyzed the candidate PLN gene in 87 patients with hypertrophic cardiomyopathy (CMH), 10 with dilated cardiomyopathy (CMD; see CMD1P, 609909), and 2 patients with restricted cardiomyopathy (RCM; see 115210). In the proband of a 2-generation family with CMH, Minamisawa et al. (2003) identified heterozygosity for a mutation in the promoter region (172405.0004) that was not found in 296 Japanese controls. Direct sequencing of the CMH-associated genes MYH7 (160760), TNNT2 (191045), and MYBPC3 (600958) in the proband revealed no additional mutation in the regions of frequent occurrence of mutations in those genes.

Kalemi et al. (2005) analyzed the promoter region and 2 exons of the PLN gene in 53 Greek patients with CMH, including 35 unrelated patients and 21 patients from 9 families, but did not find any mutations or polymorphisms. The authors concluded that PLN mutations are not associated with CMH in patients from northern Greece. Kalemi et al. (2005) noted that because 95% of identified CMH-related mutations involve 4 genes, namely MYH7, TNNT2, MYBPC3, and TNNI3 (191044), a large cohort of CMH patients would be required to identify a novel CMH-causing gene.

Medin et al. (2007) performed SSCP mutation screening and DNA sequencing of the PLN gene in 101 CMH patients and 85 CMD patients and identified a point mutation in the promoter region (172405.0005) in an 85-year-old woman with CMH that was not found in more than 100 control subjects. In the proband, additional mutations in MYH7 and MYBPC3 were excluded by SSCP and sequencing of the entire coding sequence of both genes; screening of previously reported mutations in TNNT2, TNNI3, ACTC1 (102540), and TPM1 (191010) genes was also negative.

Chiu et al. (2007) screened an Australian cohort of 252 unrelated CMH patients for mutations in calcium regulatory genes and identified heterozygosity for a nonsense mutation in the PLN gene (L39X; 172405.0002) in a 65-year-old female proband. Landstrom et al. (2011) analyzed the PLN gene in a cohort of 1,064 CMH probands and identified heterozygosity for the L39X mutation in a 58-year-old male proband, who was negative for mutation in 9 myofilament genes known to be associated with CMH and was also negative for mutation in the PRKAG2 (602743), LAMP2 (309060), and GLA (300644) genes. The L39X mutation was also found in 1 asymptomatic daughter and a granddaughter, who had CMH by echocardiography.

Landstrom et al. (2011) analyzed the PLN gene in a cohort of 1,064 CMH probands and identified heterozygosity for the L39X mutation in a 58-year-old male proband, who was negative for mutation in 9 myofilament genes known to be associated with CMH and was also negative for mutation in the PRKAG2 (602743), LAMP2 (309060), and GLA (300644) genes. The L39X mutation was also found in 1 asymtomatic daughter and a granddaughter, who had CMH by echocardiography.

Petkow-Dimitrow et al. (2011) screened 50 consecutive patients with CMH from southern Poland for the R9C (172405.0001) and L39X mutations in the PLN gene but did not find those mutations in any patients or in 50 sex- and age-matched controls with normal echocardiograms.