Sarcomere mutations in cardiomyopathy with left ventricular hypertrabeculation.

Department of Medicine, The University of Chicago, Chicago, Ill, USA.
Circulation Cardiovascular Genetics (Impact Factor: 6.73). 10/2009; 2(5):442-9. DOI: 10.1161/CIRCGENETICS.109.861955
Source: PubMed

ABSTRACT Mutations in the genes encoding sarcomere proteins have been associated with both hypertrophic and dilated cardiomyopathy. Recently, mutations in myosin heavy chain (MYH7), cardiac actin (ACTC), and troponin T (TNNT2) were associated with left ventricular noncompaction, a form of cardiomyopathy characterized with hypertrabeculation that may also include reduced function of the left ventricle.
We used clinically available genetic testing on 3 cases referred for evaluation of left ventricular dysfunction and noncompaction of the left ventricle and found that all 3 individuals carried sarcomere mutations. The first patient presented with neonatal heart failure and was referred for left ventricular noncompaction cardiomyopathy. Genetic testing found 2 different mutations in MYBPC3 in trans. The first mutation, 3776delA, Q1259fs, rendered a frame shift at 1259 of cardiac myosin-binding protein C and the second mutation was L1200P. The frameshift mutation was also found in this mother who displayed mild echocardiographic features of cardiomyopathy, with only subtle increase in trabeculation and an absence of hypertrophy. A second pediatric patient presented with heart failure and was found to carry a de novo MYH7 R369Q mutation. The third case was an adult patient with dilated cardiomyopathy referred for ventricular hypertrabeculation. This patient had a family history of congestive heart failure, including pediatric onset cardiomyopathy where 3 individuals in the family were found to have the MYH7 mutation R1250W.
Genetic testing should be considered for cardiomyopathy with hypertrabeculation.

  • International journal of cardiology 03/2014; · 6.18 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Left ventricular noncompaction (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. LVNC is classified as a rare genetic cardiomyopathy. Molecular diagnosis is a challenge for the medical community as the condition shares morphologic features of hypertrophic and dilated cardiomyopathies. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. In this report, we describe a case of a severe form of LVNC leading to death at 6 months of life. NGS sequencing using a custom design for hypertrophic cardiomyopathy panel allowed us to identify compound heterozygosity in the MYBPC3 gene (p.Lys505del, p.Pro955fs) in 3 days, confirming NGS sequencing as a fast molecular diagnosis tool. Other studies have reported neonatal presentation of cardiomyopathies associated with compound heterozygous or homozygous MYBPC3 mutations. In this family and in families in which parental truncating MYBPC3 mutations are identified, preimplantation or prenatal genetic screening should be considered as these genotypes leads to neonatal mortality and morbidity.
    European journal of medical genetics 03/2014; · 1.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Left ventricular non-compaction (LVNC) is genetically heterogeneous. It has been previously shown that LVNC is associated with defects in TAZ, DNTA, LDB3, YWHAE, MIB1, PRDM16, and sarcomeric genes. This study was aimed to investigate sarcomeric gene mutations in a Chinese population with LVNC. From 2004 to 2010, 57 unrelated Chinese patients with LVNC were recruited at Fuwai Hospital, Beijing, China. Detailed clinical evaluation was performed on the probands and available family members. DNA samples isolated from the peripheral blood of the index cases were screened for 10 sarcomeric genes, including MYH7, MYBPC3, MYL2, MYL3, MYH6, TNNC1, TNNT2, TNNI3, TPM1, and ACTC1. Seven heterozygous mutations (6 missense and 1 deletion) were identified in 7 (12 %) of the patients. These mutations were distributed among 4 genes, 4 in MYH7, and 1 each in ACTC1, TNNT2, and TPM1. Six of the mutations were novel and another one was reported previously. All mutations affected conserved amino acid residues and were predicted to alter the structure of the proteins by in silico analysis. No significant difference was observed between mutation-positive and mutation-negative patients with respect to clinical characteristics at baseline and mortality during follow-up. In conclusion, our study indicates that sarcomeric gene mutations are uncommon causes of LVNC in Chinese patients and genetic background of the disease may be divergent among the different races.
    Heart and Vessels 04/2014; · 2.13 Impact Factor