An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole‐exome sequencing (
WES), are identifying the genetic basis of disease for 25–40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WESis used. The Finding Of Rare Disease GEnes( FORGE) Canada project was a nation‐wide effort to identify mutations for childhood‐onset disorders using WES. Most children enrolled in the FORGEproject were toward the end of the diagnostic odyssey. The two primary outcomes of FORGEwere novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WESidentified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WESin the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WESenrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WESwill be paradigm altering for patients and families with rare genetic diseases.