Gender- and age-related differences in distinct phenotypes of hypertrophic cardiomyopathy-associated mutation MYBPC3-E334K.

The mutation MYBPC3-E334K is a culprit mutation of hypertrophic cardiomyopathy (HCM). The pathogenicity of MYBPC3-E334K is conflicting in ClinVar because of the limited segregation data and the relatively high frequency in gnomAD (0.03% overall, with 0.3% in East Asians and 0.8% in Japanese). The main aim is to clarify the clinical importance and phenotype-genotype correlations in subjects with or without MYBPC3-E334K alone. The prevalence of MYBPC3-E334K was sequenced in 1017 HCM unrelated probands. The clinical features, morphology phenotypes, and electrical phenotypes were further analyzed according to the phenotype and genotype status in families with single-mutation MYBPC3-E334K. Nine of 1017 (0.88%) unrelated HCM probands were detected harboring MYBPC3-E334K, and three of them harbored a second variant in sarcomere protein gene. Family study and co-segregation analyses indicated that patients with single-mutation MYBPC3-E334K showed autosomal dominant mode of inheritance with incomplete penetrance. The overall disease penetrance was 52.6%, and the disease penetrance was higher in males than in females (100% in men vs 25% in women, p = 0.003). The mean age at diagnosis of males was approximately 25 years younger than females (36.57 ± 18.65 vs 62.33 ± 12.10, p = 0.062). The variant MYBPC3-E334K was classified as a likely pathogenic variant, and a second sarcomere variant did not reveal obvious cumulative effects. The patients harboring single-mutation MYBPC3-E334K had incomplete penetrance, and males demonstrated higher penetrance and early onset HCM than females. A second sarcomere variant did not reveal obvious cumulative effects.

Investigation of myocardial dysfunction using three-dimensional speckle tracking echocardiography in a genetic positive hypertrophic cardiomyopathy Chinese family.

BACKGROUND: We previously reported four heterozygous missense mutations of MYH7, KCNQ1, MYLK2, and TMEM70 in a single three-generation Chinese family with dual Long QT and hypertrophic cardiomyopathy phenotypes for the first time. However, the clinical course among the family members was various, and the potential myocardial dysfunction has not been investigated. OBJECTIVES: The objective of this study was to investigate the echocardiographic and electrocardiographic characteristics in a genetic positive Chinese family with hypertrophic cardiomyopathy and further to explore the association between myocardial dysfunction and electric activity, and the identified mutations. METHODS: A comprehensive echocardiogram - standard two-dimensional Doppler echocardiography and three-dimensional speckle tracking echocardiography - and electrocardiogram were obtained for members in this family. RESULTS: As previously reported, four missense mutations - MYH7-H1717Q, KCNQ1-R190W, MYLK2-K324E, and TMEM70-I147T - were identified in this family. The MYH7-H1717Q mutation carriers had significantly increased left ventricular mass indices, elevated E/e' ratio, deteriorated global longitudinal stain, but enhanced global circumferential and radial strain compared with those in non-mutation patients (all p<0.05). The KCNQ1-R190W carriers showed significantly prolonged QTc intervals, and the MYLK2-K324E mutation carriers showed inverted T-waves (both p<0.05). However, the TMEM70-I147T mutation carriers had similar echocardiography and electrocardiographic data as non-mutation patients. CONCLUSIONS: Three of the identified four mutations had potential pathogenic effects in this family: MYH7-H1717Q was associated with increased left ventricular thickness, elevated left ventricular filling pressure, and altered myocardial deformation; KCNQ1-R190W and MYLK2-K324E mutations were correlated with electrocardiographic abnormalities reflected in long QT phenotype and inverted T-waves, respectively.

Clinical and molecular characterization of seven patients with Danon disease.

Danon disease is an X-linked glycogen storage disease characterized by skeletal myopathy, cardiomyopathy and intellectual impairment. It is caused by a loss-of-function mutation in the lysosome-associated membrane protein-2 (LAMP2) gene. In the present study, exon and boarding intron analysis of 96 cardio disease-associated genes was performed in 770 patients with hypertrophic cardiomyopathy (HCM) using second-generation sequencing. Next, the identified mutations were confirmed in family members of the patients and 300 healthy controls. Detailed clinical, electrocardiographic (ECG) and echocardiographic findings were recorded. A pathogenic mutation in LAMP2 was identified in 7 patients who phenotypically presented with HCM. A total of four patients had a fragmented QRS complex (fQRS) on surface ECG. In addition, two patients presented with ventricular preexcitation with a short PR interval. Compared with the patients with protein kinase AMP-activated non-catalytic subunit γ2 syndrome and Fabry disease, the 7 patients with Danon disease presented at an earlier age, had a smaller left atrial size, a thinner maximal left ventricular wall thickness and a lower probability of pacemaker implantation. Compared with 12 sex- and age-matched patients with sarcomere-protein mutations, the 4 patients with Danon disease had a lower left ventricular outflow tract gradient and worse diastolic function. The present study provided a comprehensive comparison of different pathologies presenting with HCM and reported on features of early-onset Danon disease, including the characteristic preexcitation and fQRS on ECG. This may provide valuable information that may be utilized for the early diagnosis and treatment of patients with Danon disease. The present study was registered as a clinical trial with ClinicalTrials.gov (Sep. 2, 2016; registry no. NCT02888132).