Locus Heterogeneity
Locus heterogeneity describes the phenomenon where a single disease can be caused by multiple different loci across different patients. Over the last few decades, studies performing linkage analysis followed by positional cloning have identified many genes as being responsible for various inherited diseases; the Online Mendelian Inheritance in Man (OMIM) database currently records 3,000 genes as being disease-causing (http://www.ncbi.nlm.nih.gov/omim). This also suggests that the majority of the remaining diseases without known associations with genes have not been amenable to classical approaches and will likely display extensive genetic heterogeneity. Increasing the size of the patient cohort will increase the power to discover variants, as shown in Fig. 3. Pathway or gene ontology analyses can also be performed to link the mutated genes into certain functional categories-there are several publicly available tools for this purpose. A good example of this method is the aforementioned study on PHAII-the authors initially identified KLHL3 from WES of 11 patients and subsequently considered KLHL3's presumed functional partner, CUL3, as a potential gene candidate. Extending the screening to 52 patients, KLHL3 was found to be mutated in 24 patients (46.2%) and CUL3 in another 17 patients (32.7%), explaining a total of 78.8% of the entire patient set. Another possible approach is to re-evaluate the clinical diagnosis of patients in the cohort by correlating subtle differences of clinical measurements and genetic variants in order to focus the analysis on a more clinically homogeneous set of patients as a separate cohort.