title: 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.
authors.affiliation: Stanford Center for Inherited Cardiovascular Disease, Stanford University Medical Center, Stanford, California 94305, USA. ccaleshu@stanfordmed.org
authors.forename: Colleen
authors.initials: C
authors.lastname: Caleshu
authors.forename: Rahul
authors.initials: R
authors.lastname: Sakhuja
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.forename: Nelson B
authors.initials: NB
authors.lastname: Schiller
authors.forename: Philip C
authors.initials: PC
authors.lastname: Ursell
authors.forename: Celeste
authors.initials: C
authors.lastname: Eng
authors.forename: Teresa
authors.initials: T
authors.lastname: De Marco
authors.forename: Dana
authors.initials: D
authors.lastname: McGlothlin
authors.forename: Esteban González
authors.initials: EG
authors.lastname: Burchard
authors.forename: J Eduardo
authors.initials: JE
authors.lastname: Rame
mesh_terms: D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002313:Cardiomyopathy, Restrictive / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012518:Sarcomeres / Q000235:genetics*