Similar to the procedure presented in the original publication (11), we assessed the number of candidate genes by utilizing variants from one, two, three or four subjects. When examining one subject, we were able to identify a set of 159 candidate genes. When examining two subjects, the number of candidate genes dropped substantially to 13. When three subjects were examined, only six candidate genes remained. When four subjects were examined, we can trim down the list of candidate genes to four (HYDIN, KCNJ12, COL4A6, MYH3). If we subsequently utilize SIFT scores (9) or PolyPhen scores (10) to evaluate the mutations in these four genes, we can further exclude KCNJ12 and COL4A6 as the causal genes. This analysis demonstrated that combined analysis of multiple genomes helped identify the causal gene for dominant Mendelian diseases, when all patients carry causal mutations at the same gene. However, we caution that for complex diseases or for Mendelian diseases where multiple causal genes exist, users need to consider the possibility of genetic heterogeneity in data analysis.
