Genetics of congenital heart disease: a narrative review of recent advances and clinical implications

Wang

et al. 2022

JAHA

Background Dilated cardiomyopathy (DCM), characterized by progressive left ventricular enlargement and systolic dysfunction, is the most common type of cardiomyopathy and a leading cause of heart failure and cardiac death. Accumulating evidence underscores the critical role of genetic defects in the pathogenesis of DCM, and >250 genes have been implicated in DCM to date. However, DCM is of substantial genetic heterogeneity, and the genetic basis underpinning DCM remains elusive in most cases. Methods and Results By genome‐wide scan with microsatellite markers and genetic linkage analysis in a 4‐generation family inflicted with autosomal‐dominant DCM, a new locus for DCM was mapped on chromosome 15q13.1–q13.3, a 4.77‐cM (≈3.43 Mbp) interval between markers D15S1019 and D15S1010, with the largest 2‐point logarithm of odds score of 5.1175 for the marker D15S165 at recombination fraction (θ)=0.00. Whole‐exome sequencing analyses revealed that within the mapping chromosomal region, only the mutation in the KLF13 gene, c.430G>T (p.E144X), cosegregated with DCM in the family. In addition, sequencing analyses of KLF13 in another cohort of 266 unrelated patients with DCM and their available family members unveiled 2 new mutations, c.580G>T (p.E194X) and c.595T>C (p.C199R), which cosegregated with DCM in 2 families, respectively. The 3 mutations were absent from 418 healthy subjects. Functional assays demonstrated that the 3 mutants had no transactivation on the target genes ACTC1 and MYH7 (2 genes causally linked to DCM), alone or together with GATA4 (another gene contributing to DCM), and a diminished ability to bind the promoters of ACTC1 and MYH7 . Add, the E144X‐mutant KLF13 showed a defect in intracellular distribution. Conclusions This investigation indicates KLF13 as a new gene predisposing to DCM, which adds novel insight to the molecular pathogenesis underlying DCM, implying potential implications for prenatal prevention and precision treatment of DCM in a subset of patients.

Section: Discussionsupporting

confidence: 84%

KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy

Wang

et al. 2022

JAHA

“…Congenital heart defects (CHD) are the most common birth defects and comprise various diseases, including septal defects or valve and chamber malformations [ 99 ]. CHD can be caused by both genetic and non-genetic factors.…”

Section: Zebrafish To Study Human Cardiac and Vessel Alterationsmentioning

confidence: 99%

Zebrafish as a Model of Cardiac Pathology and Toxicity: Spotlight on Uremic Toxins

Coppola

Lombari

Mazzella

et al. 2023

IJMS

Chronic kidney disease (CKD) is an increasing health care problem. About 10% of the general population is affected by CKD, representing the sixth cause of death in the world. Cardiovascular events are the main mortality cause in CKD, with a cardiovascular risk 10 times higher in these patients than the rate observed in healthy subjects. The gradual decline of the kidney leads to the accumulation of uremic solutes with a negative effect on every organ, especially on the cardiovascular system. Mammalian models, sharing structural and functional similarities with humans, have been widely used to study cardiovascular disease mechanisms and test new therapies, but many of them are rather expensive and difficult to manipulate. Over the last few decades, zebrafish has become a powerful non-mammalian model to study alterations associated with human disease. The high conservation of gene function, low cost, small size, rapid growth, and easiness of genetic manipulation are just some of the features of this experimental model. More specifically, embryonic cardiac development and physiological responses to exposure to numerous toxin substances are similar to those observed in mammals, making zebrafish an ideal model to study cardiac development, toxicity, and cardiovascular disease.

Current Opinion in Cardiology

“…BAV was shown to be heritable and have genetic contributors [16]. Subsequent work has demonstrated that BAV has a heterogeneous mix of causes, and multiple genes have been associated with BAV using positional cloning, genome-wide association studies (GWAS) and next-generation sequencing (NGS) [17,18]. Functional genomics using cellular and animal genetic models have been used to validate the pathogenicity of genetic variants and explore underlying mechanisms [19].…”

Section: Genetics Of Bicuspid Aortic Valvementioning

confidence: 99%

Genetics of aortic valve disease

Ackah

Yasuhara

Garg

2023

Self Cite

Purpose of reviewAortic valve disease is a leading global cause of morbidity and mortality, posing an increasing burden on society. Advances in next-generation technologies and disease models over the last decade have further delineated the genetic and molecular factors that might be exploited in development of therapeutics for affected patients. This review describes several advances in the molecular and genetic understanding of AVD, focusing on bicuspid aortic valve (BAV) and calcific aortic valve disease (CAVD).Recent findingsGenomic studies have identified a myriad of genes implicated in the development of BAV, including NOTCH1, SMAD6 and ADAMTS19, along with members of the GATA and ROBO gene families. Similarly, several genes associated with the initiation and progression of CAVD, including NOTCH1, LPA, PALMD, IL6 and FADS1/2, serve as the launching point for emerging clinical trials.SummaryThese new insights into the genetic contributors of AVD have offered new avenues for translational disease investigation, bridging molecular discoveries to emergent pharmacotherapeutic options. Future studies aimed at uncovering new genetic associations and further defining implicated molecular pathways are fuelling the new wave of drug discovery.