text: In Mendelian disorders of large effect, findings thus far suggest one or a very small number of variants within coding genes underlie the entire condition. Because of the severity of these disorders, the few causal variants are presumed to be extremely rare or novel in the population, and would be missed by any standard genotyping assay. Exome sequencing provides high coverage variant calls across coding regions, which are needed to separate true variants from noise. A successful model of Mendelian gene discovery involves the discovery of de novo variants using trio sequencing, where parents and proband are genotyped.