Olson et al. (2002) reported a consanguineous family in which 3 sibs had presented with childhood-onset CMH characterized by midcavitary left-ventricular hypertrophy (CMH8; 608751). Both parents had completely normal hearts in their 40s. Mutation screening in a surviving affected sib revealed a homozygous missense G-to-A point mutation at codon 143 of the MYL3 gene, resulting in a glutamic acid-to-lysine (E143K) substitution. Heterozygotes had normal hearts. Sequence alignment of myosin essential light chains demonstrated high conservation of glutamic acid at position 143 across species. The E143K mutation was absent from 150 normal control DNA samples. The authors concluded that this was a true autosomal recessive form of CMH8.
In a 22-year-old woman from El Salvador with cardiomyopathy, Caleshu et al. (2011) sequenced the exons and exon-intron boundaries of 8 known cardiomyopathy-associated genes and identified homozygosity for the E143K mutation in the MYL3 gene. The patient was also found to be heterozygous for a G57E polymorphism in the MYL2 gene (160781); her asymptomatic 45-year-old mother, who had a normal transthoracic echocardiogram, electrocardiogram, and physical examination, was heterozygous for both the E143K mutation in MYL3 and the G57E polymorphism in MYL2. The patient, who had a prior diagnosis of childhood asthma, presented with worsening dyspnea and fatigue over the previous year, and transthoracic echocardiogram revealed severe biatrial enlargement with preserved biventricular systolic function and no left ventricular hypertrophy or valvular disease; Doppler evaluation suggested advanced left ventricular diastolic dysfunction. Left and right heart catheterization showed elevated filling pressures bilaterally, with a prominent y-descent, a suggestion of a 'dip-and-plateau,' and ventricular concordance, all features described in restrictive cardiomyopathy (RCM). Right ventricular endomyocardial biopsy revealed marked myocyte hypertrophy and myofiber disarray with interstitial fibrosis. The patient went on to develop recurrent syncope and had an automatic implantable cardiac defibrillator placed; she underwent orthotopic heart transplantation 6 months after diagnosis with cardiomyopathy.
