A high risk phenotype of hypertrophic cardiomyopathy associated with a compound genotype of two mutated β-myosin heavy chain genes

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease that is in most cases familial and transmitted in a dominant fashion. The most frequently affected gene codes for the cardiac (ventricular) beta-myosin heavy chain. We have investigated the genetic cause of an isolated case of HCM, which was marked by an extremely severe phenotype and a very early age of onset. HCM is normally not a disease of small children. The proband was a boy who had suffered cardiac arrest at the age of 6.5 years (resuscitation by cardioconversion). Upon screening of the beta-myosin heavy chain gene as a candidate, two missense mutations, one in exon 19 (Arg719Trp) and a second in exon 12 (Met349Thr), were identified. The Arg719Trp mutation was de novo, as it was not found in the parents. In contrast, the Met349Thr mutation was inherited through the maternal grandmother. Six family members were carriers of this mutation but only the proband was clinically affected. Segregation and molecular analysis allowed us to assign the Met349Thr mutation to the maternal and the Arg719Trp de novo mutation to the paternal beta-myosin allele. Thus, the patient has no normal myosin. We interpret these findings in terms of compound heterozygosity of a dominant (Arg719Trp) and a recessive (Met349Thr) mutation. Whereas a single mutated Arg719Trp allele would be sufficient to cause HCM, the concurrent Met349Thr mutation alone does not apparently induce the disease. Nevertheless, it conceivably contributes to the particularly severe phenotype.

Hypertrophic Cardiomyopathy: Low Frequency of Mutations in the β-Myosin Heavy Chain (MYH7) and Cardiac Troponin T (TNNT2) Genes among Spanish Patients

“…These data suggest that this is a de novo mutation linked to a severe form of HC. De novo mutations in the MYH7 gene have previously been described in at least two patients (30,31 ). In addition to this de novo mutation, we found a previously described mutation in a 44-year-old woman with a mild form of HC and a family history of sudden death.…”

Molecular genetics of familial hypertrophic cardiomyopathy (FHC)

“…As expected, the latter two subjects exhibited a significantly greater left ventricular hypertrophy than did the other affected subjects, although the double mutation was not lethal. Compound heterozygotes for the MYH7 gene resulting in FHC have also been described (Nishi et al 1995;Jeschke et al 1998). Most studies on FHC resulting from mutations in the MYH7 gene indicate that the mutated protein gets incorporated into the sarcomere and exerts a dominant negative effect, leading to a compensatory hypertrophic response.…”

Low-density DNA microarrays are versatile tools to screen for known mutations in hypertrophic cardiomyopathy

“…DNA was isolated from blood lymphocytes as described [Jeschke et al, 1998]. Heat stable GoldStar DNA Polymerase (Eurogentec, Seraing, Belgium) was used according to the supplier s protocol to obtain amplicons representing exons 9, 12, 13, 16b (3′ half of exon 16), 19, 23, and 34 of MYH7, exon 25 of MYBPC3, exon 8 and 9 of TNNT2, and exon 5 of TPM1.…”

“…The cycling conditions were 4 min at 94°C, 30 cycles with 35 sec at 94°C, 60°C, and 72°C, respectively, and 10 min at 72°C (cycler: Techne Progene, Labtech International, Burkhardtsdorf, Germany). For more details on the PCR protocol see Jeschke et al [1998]. About 5 ng of the PCR product was used to reamplify the DNA in the presence of 40 µM biotin-16-dUTP (Roche, Mannheim, Germany), 80 µM dTTP, 100 µM each of dATP, dCTP and dGTP, 0.2 µM (or 30 ng) primer, and 0.625 units of Qiagen Taq Polymerase, in Qiagen PCR reaction buffer (Qiagen, Hilden, Germany), for 20 cycles as described above.…”