Molekulare und genetische Medizin

Objectives: Cardiomyopathies are diseases of heart muscle caused by mutations in cytoskeletal genes. Disease severity and penetrance vary greatly among patients carrying the same mutation(s) and single-gene variants often do not reliably predict cardiomyopathy phenotypes.

Background: The chromosome 10q21-q23 locus was previously associated to familial dilated cardiomyopathy (DCM), arrhythmias, heart failure, Wolff-Parkinson-White (WPW) syndrome, mitral valve prolapse (MVP) and/or mitral regurgitation (MR). However, the exact variants responsible for heterogeneous DCM and arrhythmia phenotypes remained unknown.

Methods: A large family of 62 members was re-studied using whole exome and direct sequencing. Phenotype- genotype correlation and systems genetics analysis were performed.

Results: We identified missense KCNMA1-M744T, ANXA11-I457V, and DYDC2-P123R variants at 10q21-q23. The proband and ten family members carried ANXA11-I457V and DYDC2-P123R identified in cis (digenic heterozygosity). Seven digenic carriers were affected including DCM (n = 3), heart failure (n = 1), left ventricular dysfunction (n = 3), arrhythmia (n = 2), MVP (n=2) and MR (n = 3). A single KCNMA1-M744T variant was identified in 11 individuals, including 4 affected with MVP or MR (n = 4), ventricular arrhythmia (n = 2), and WPW (n = 1). All three variants were identified in three family members and all were affected. Rare variants in cardiomyopathy-related genes such as CORIN-I52V, TTN-S21630P, TRPM7-Y537H, OTX1-H301del and FLNC- N47S were identified in affected individuals.

Conclusions: This study facilitated the family-based predictive and personalized approach in identifying disease causative basis in patients with familial DCM and their relatives “at risk”. Different variant combinations of trans- KCNMA1-M744T and cis-ANXA11-I457V and DYDC2-P123R identified at 10q21-q23 underlie the clinical heterogeneity of familial DCM. Rare variants identified beyond the 10q21-q23 were predicted to modify the function of KCNMA1, ANXA11, and DYDC2 that may serve as the genetic modifiers in intra- and inter-familial phenotypic variability.

Researcher have paid more and more attention to the mechanisms by which intestinal flora affect the health and wellbeing of the host, and to what extent intestinal flora contribute to illness in the general population. Researchers also intend to determine the changes of intestinal flora over time, and the consequences of those changes for aging. This review will focus on the role that intestinal bacteria play in health and aging by providing a landscape of the intestinal flora with age, as well as the clinical signs/symptoms and mechanisms by which intestinal flora may affect aging. We anticipate that by exploring the relationship between intestinal flora and the host, it may ultimately be possible to identify particular classes of intestinal flora that affect aging.