As the availability of advanced molecular testing like whole exome and genome sequencing expands, it comes with the added complication of interpreting inconclusive results, including determining the relevance of variants of uncertain significance or failing to find a variant in an otherwise suspected specific genetic disorder. This complication necessitates the use of alternative testing methods to gather more information in support of, or against, a particular genetic diagnosis. Therefore, new genome-wide approaches, including DNA epigenetic testing, RNA sequencing, and metabolomics, are increasingly being used to increase the diagnostic yield when used in conjunction with more conventional genetic tests.