Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy

Abstract

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

Figure 1

Right ventricular endomyocardial biopsy from Patient 1. At high magnification the hypertrophied muscle fibers (dark pink) are separated by abundant interstitial fibrosis (light pink). Coursing in various directions, the myofibers in some areas are oriented orthogonally, characteristic of myofiber disarray. Hematoxylin and eosin, calibration bar = 45 microns. Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.

Figure 2

Pedigree from Patient 1 (A) and Patient 2 (B) demonstrating incomplete dominance, reduced penetrance, and variable expressivity.

Figure 3

Alignment of MYL2 (A) and TPM1 (B) mutation-flanking regions showing evolutionary conservation of the mutated residues and neighboring amino acids across and within species.