Analysis of De Novo Mutations in Sporadic Cardiomyopathies Emphasizes Their Clinical Relevance and Points to Novel Candidate Genes

The vast majority of cardiomyopathies have an autosomal dominant inheritance; hence, genetic testing is typically offered to patients with a positive family history. A de novo mutation is a new germline mutation not inherited from either parent. The purpose of our study was to search for de novo mutations in patients with cardiomyopathy and no evidence of the disease in the family. Using next-generation sequencing, we analyzed cardiomyopathy genes in 12 probands. In 8 (66.7%), we found de novo variants in known cardiomyopathy genes (TTN, DSP, SCN5A, TNNC1, TPM1, CRYAB, MYH7). In the remaining probands, the analysis was extended to whole exome sequencing in a trio (proband and parents). We found de novo variants in genes that, so far, were not associated with any disease (TRIB3, SLC2A6), a possible disease-causing biallelic genotype (APOBEC gene family), and a de novo mosaic variant without strong evidence of pathogenicity (UNC45A). The high prevalence of de novo mutations emphasizes that genetic screening is also indicated in cases of sporadic cardiomyopathy. Moreover, we have identified novel cardiomyopathy candidate genes that are likely to affect immunological function and/or reaction to stress that could be especially relevant in patients with disease onset associated with infection/infestation

Can Circulating Cardiac Biomarkers Be Helpful in the Assessment of LMNA Mutation Carriers?

Mutations in the lamin A/C gene are variably phenotypically expressed; however, it is unclear whether circulating cardiac biomarkers are helpful in the detection and risk assessment of cardiolaminopathies. We sought to assess (1) clinical characteristics including serum biomarkers: high sensitivity troponin T (hsTnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in clinically stable cardiolaminopathy patients, and (2) outcome among pathogenic/likely pathogenic lamin A/C gene (LMNA) mutation carriers. Our single-centre cohort included 53 patients from 21 families. Clinical, laboratory, follow-up data were analysed. Median follow-up was 1522 days. The earliest abnormality, emerging in the second and third decades of life, was elevated hsTnT (in 12% and in 27% of patients, respectively), followed by the presence of atrioventricular block, heart failure, and malignant ventricular arrhythmia (MVA). In patients with missense vs. other mutations, we found no difference in MVA occurrence and, surprisingly, worse transplant-free survival. Increased levels of both hsTnT and NT-proBNP were strongly associated with MVA occurrence (HR > 13, p ≤ 0.02 in both) in univariable analysis. In multivariable analysis, NT-proBNP level > 150 pg/mL was the only independent indicator of MVA. We conclude that assessment of circulating cardiac biomarkers may help in the detection and risk assessment of cardiolaminopathies

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

<div><p><i>TTN</i> gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in <i>TTN</i> in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the <i>TTN</i> gene. Truncating mutations were followed up by segregation study among family members. We identified 16 <i>TTN</i> truncating variants (<i>TTN</i> trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, <i>TTN</i> truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.</p></div

Comparison of clinical data on <i>TTN</i> trunc positive versus <i>TTN</i> trunc negative DCM probands.

<p>Comparison of clinical data on <i>TTN</i> trunc positive versus <i>TTN</i> trunc negative DCM probands.</p

List of <i>TTN</i> truncating variants identified in the study group annotated to transcript NM_001267550.2.

<p>List of <i>TTN</i> truncating variants identified in the study group annotated to transcript NM_001267550.2.</p

Clinical characteristics of affected and not affected <i>TTN</i> trunc positive relatives.

<p>Clinical characteristics of affected and not affected <i>TTN</i> trunc positive relatives.</p

Kaplan-Meier cumulative survival curves for SAE (HF death, OHT or LVAD) in 46 carriers of <i>TTN</i> truncating variants, males and females, p = 0.018, log-rank test = -2.37.

<p>Kaplan-Meier cumulative survival curves for SAE (HF death, OHT or LVAD) in 46 carriers of <i>TTN</i> truncating variants, males and females, p = 0.018, log-rank test = -2.37.</p