In the past 10-15 years the molecular basis for several monogenic cardiac disorders such as cardiomyopathies, arrhythmias, and complex congenital heart has been discovered. These milestone publications unravelled pathophysiologic pathways for of these disorders and thereby allowed a concept of "final common disease pathways" through the identification of specific cellular components or disease target proteins. The complexity of monogenic disorders was enhanced by the identification that a series of many genes is involved in each disease and that even herein, each patient may have a particular gene variant ("familial mutation") causing the phenotype. Thus, a rare disease paradigm (rare mutation > rare disease) has been evolved. However, even in a single family with one gene mutation the phenotype of mutation carriers may have a widespread variability that may resemble polygenic features.

Due to the recent identification of common, non-synonymous polymorphic variants (SNPs) and haplotypes in cardiovascular genes that have been associated with cardiovascular Mendelian traits, current investigations focus on the characterization of associations between common variants and common disease. In this line, identification of genetic susceptibility factors for multi-factorial diseases (e.g., sudden cardiac death) still remains a challenging endeavour and will most likely require a combination of a multitude and power of strategies. These encompass rapid availability of the genomic and coding sequences of various species as well as high-throughput technologies for the determination of sequence variation, transcriptional and proteomic profiles. As well, large clinical and well-phenotyped patient populations are required to elucidate complex disorders within an integrated concept ("integrated genomic profiling") that strictly combines clinical information and detailed molecular analysis. These strategies are accompanied by the development of novel statistical concepts with the need to include complex interactions between multiple genes, individual and environmental factors. Furthermore, the inclusion of prospective study samples will be pivotal for the success of such studies, since they allow the evaluation of the genetic risk contributors on a population-based level.

Based on these considerations, the major areas of focus in Dr. Schulze-Bahr’s group at the Munster site are

• monogenic basis on the cardiovascular phenotypes that are obviously genetic; these disorders include
              - cardiomyopathies,
              - supraventricular and ventricular arrhythmias,
              - congenital heart disease;
  The definition of the entire genetic heterogeneity of monogenic cardiovas­cu­lar disease genes also will allow to define the extent of the genetic basis of spo­radic (non-familial) disorders, since for some diseases (e.g., complex heart disease) the majority of cases are non-familial;
• examples of Mendelian cardiovascular disorders being under current investigation are various types of ventricular arrhythmias (such as LQTS, SQTS, Brugada syndrome), cardiomyopathies (such as ARVC), sudden infant death syndrome (SIDS),  and atrial septal defect (ASD-II);
• deciphering the haplotype structure of relevant cardiovascular genes and test them for their quantitative phenotype modulation in selected patient samples, e.g., twins, patients with acquired cardiovascular disease, or families with the same gene mutation.
• functional relevance of identified non-synonymous SNPs in cardiovascular genes, e.g., the IKr potassium channel gene HERG/KCNH2, and elaborate their effects on myocellular electrophysiology

The group will add one of the largest sample populations of inherited patients in Europe with a high risk for sudden cardiac death. Since 1994, we were able to collect genetic and clinical information on more than 4,000 individuals, including ~700 unrelated probands with long-QT syndrome, >140 probands with Brugada syndrome, and > 160 probands with ARVC.

The aims will be addressed by 

I).   Genome-wide linkage analyses in selected families using highly polymorphic micro­satellite markers;
II).  Haplotype construction of parental chromosomes, determination of break-points of chromosomal recombination
III). Co-segregation analysis, MLINK evaluation of lod score
IV).  Positional cloning and genome investigation of target tissue-specific genes in chromosomal candidate region
V).   Functional analysis of mutant target proteins, complementation of functional defects
VI).  Genotype-phenotype relationship, investigation of genetic and non-genetic phenotype-related variation.