Deciphering monogenic cardiovascular diseases
Our projects aim to identify and interpret genetic variations underlying inherited cardiac diseases (ICD), including cardiomyopathies, channelopathies, congenital heart defects, coronary artery disease, myocardial infarction, and primary arrhythmogenic disorders.
Our long-term objective is to elucidate the underlying molecular mechanism of inherited cardiac diseases in families from Germany and Pakistan and apply this knowledge to improve the lives of patients through new diagnostic and therapeutic options.
Coronary artery disease (CAD) and its sequelae myocardial infarction (MI) are the leading cause of death in the Western world. Genome wide association studies have reported many common variants and risk loci that affect coronary artery disease, but they are limited in linking these variants with phenotypic consequences.
The importance of genetic predisposition to CAD and MI is best documented by the predictive value of a positive family history. However, the genetic causes for familial clustering of MI are less clear. Next-Generation Sequencing in families with several affected individuals has revolutionized variant identification in Mendelian diseases, but can also successfully be applied to more complex phenotypes such as CAD and MI.
In this project, we applied whole-exome sequencing and co-segregation analysis in one MI-family and identified a heterozygous c.1324G>T alteration resulting in a substitution of p. V442L in exon 6 of EPHA2, a gene located at the 1p36 locus in humans, which is linked to MI. The mutated residue is highly conserved, and its substitution is predicted to be pathogenic by several in-silico tools. EphA2 receptor plays important role in regulating the cellular events after permanent coronary occlusion and its entanglement in the progression of ischemic cardiomyopathy. Further functional studies are ongoing to understand the underlying pathomechanism.
The identification of a likely pathogenic variant in EPHA2 may give us new information about the involvement of ephrin receptors in the pathomechanism of CAD.
Congenital heart defect or CHD refers to structural abnormalities of the heart and blood vessels that occur during cardiac development and represents a broad spectrum of malformations, including ventricular septal defect (VSD), atrial septal defect (ASD), pulmonary stenosis (PS), patent ductus arteriosus (PDA), tetralogy of Fallot (TOF), coarctation (Coarc), transposition of the great arteries (TGA) and aortic stenosis (AoS).
CHD is common and its etiology is complex as both genetic and environmental factors can perturb heart development leading to heart abnormalities.
Identifying genetic variants in affected families is the key step for better understanding the etiology of this disease.
Hence, in this project, we are using next-generation sequencing technologies to investigate large Pakistani families to identify gene variants, and modifiers, underlying CHD.
These findings will have an impact in understanding the etiology of CHD, paving the way for further research and – in long-term – towards therapy.