However, these associations were only found after massively increasing cohort sizes and marker densities, meaning that the vast majority of the associated risk factors have small effects and that they are of no diagnostic and prognostic relevance. Moreover, many markers were found to be located in noncoding sequences, and thus, very few provided novel insights into the underlying pathogenetic mechanisms. Ironically, therefore, very shortly after this “breakthrough,” there is growing support for the notion that for most common disorders, the CDCV hypothesis must be wrong.1,2 This is certainly Inhibitors,research,lifescience,medical true for mental retardation (MR) – the biggest unsolved problem of clinical genetics and the largest socioeconomic

burden of health care – where most severe forms are due to defined chromosomal abnormalities or single gene defects, instead Inhibitors,research,lifescience,medical of resulting from multifactorial inheritance, ie, the interaction of many different gene variants and environmental factors. However, there is increasing evidence that single gene defects also play a significant, previously underestimated, role in other complex disorders. This has led to growing uneasiness about the Inhibitors,research,lifescience,medical validity of the idea that GWAS is the preferred approach for identifying

sequence variants in the human genome that predispose to, or cause, disease. Moreover, it has raised serious doubts about the strategy, first proposed in the early 1990s and uncritically adopted by leading genome centers worldwide, to focus exclusively on complex

disorders. After the introduction of massive parallel next-generation Inhibitors,research,lifescience,medical sequencing techniques, there are now indications for a paradigm shift in this field, with a renewed focus on single gene disorders. At a recent meeting,3 two groups reported Inhibitors,research,lifescience,medical on their RAD001 efforts to unravel the molecular basis of Mendelian disorders by sequencing all exons in the genomes of patients and their unaffected parents. Moreover, leading genome researchers expressed their belief that instead of GWAS, whole genome sequencingbased, large-scale elucidation of single gene disorders will be the strategy of choice for shedding more light on the molecular architecture of common disorders. In the late 1980s, before common disorders were proclaimed as the central target of genome research, along second with overly optimistic assumptions about the medical implications of this research, the revolutionary and costly project to elucidate the structure of the human genome had been justified by the prospect that it would lead to unambiguous diagnosis, prevention, and, eventually, therapies for severe Mendelian disorders. Now, almost 20 years after the official commencement of the Human Genome Project, and 6 years after its completion, it appears that genome research is coming around full circle by once again focusing on single gene defects. Single gene defects are important for health care Single gene defects have significance in their own right.