Genetic Study in Left Ventricular Noncompaction

Background—Left ventricular noncompaction (LVNC) has since been classified as a primary genetic cardiomyopathy, but the genetic basis is not fully evaluated. The aim of the present study was to identify the genetic spectrum using next-generation sequencing and to evaluate genotype–phenotype correlations in LVNC patients. Methods and Results—Using next-generation sequencing, we targeted and sequenced 73 genes related to cardiomyopathy in 102 unrelated LVNC patients. We identified 43 pathogenic variants in 16 genes in 39 patients (38%); 28 were novel variants. Sarcomere gene variants accounted for 63%, and variants in genes associated with channelopathies accounted for 12%. MYH7 and TAZ pathogenic variants were the most common, and rare variant collapsing analysis showed variants in these genes contributed to the risk of LVNC, although patients carrying MYH7 and TAZ pathogenic variants displayed different phenotypes. Patients with pathogenic variants had early age of onset and more severely decreased left ventricular ejection fractions. Survival analysis showed poorer prognosis in patients with pathogenic variants, especially those with multiple variants: All died before their first birthdays. Adverse events were noted in 17 patients, including 13 deaths, 3 heart transplants, and 1 implantable cardioverter-defibrillator insertion. Congestive heart failure at diagnosis and pathogenic variants were independent risk factors for these adverse events. Conclusions—Next-generation sequencing revealed a wide spectrum of genetic variations and a high incidence of pathogenic variants in LVNC patients. These pathogenic variants were independent risk factors for adverse events. Patients harboring pathogenic variants showed poor prognosis and should be followed closely

Clinicopathological and Genetic Profiles of Cases with Myocyte Disarray—Investigation for Establishing the Autopsy Diagnostic Criteria for Hypertrophic Cardiomyopathy

Myocyte disarray of >10% in the heart is broadly accepted as a diagnostic pitfall for hypertrophic cardiomyopathy (HCM) at postmortem. The present study aims to propose an additional diagnostic criterion of HCM. Heart specimens from 1387 serial forensic autopsy cases were examined. Cases with myocyte disarray were extracted and applied to morphometric analysis to determine the amount of myocyte disarray. Comprehensive genetic analysis by using next-generation sequencing was subsequently applied for cases with myocyte disarray. Fifteen cases with myocyte disarray were extracted as candidate cases (1.1%, 11 men and 4 women, aged 48–94 years). In terms of the cause of death, only 2 cases were cardiac or possible cardiac death, and the other was non-cardiac death. Six cases showed myocyte disarray of >10% and 3 cases showed myocyte disarray of 5% to 10%. The other 6 cases showed myocyte disarray of <5%. Nine rare variants in 5 HCM-related genes (MYBPC3, MYH7, MYH6, PRKAG2, and CAV3) were found in 8 of 9 cases with myocyte disarray of >5%. The remaining 1 and 6 cases with myocyte disarray of <5% did not have any such variant. Myocyte disarray of >5% with rare variants in related genes might be an appropriate postmortem diagnostic criterion for HCM, in addition to myocyte disarray of 10%