Mitigating Genetic Diagnostic Errors and Unwarranted Cascade Testing: Two Illustrative Cases

Introduction: Genetic testing has revolutionized the clinical landscape by enabling rapid diagnosis, promoting translational research, and improving chances for actionability. With plummeting sequencing costs, Whole Genome Sequencing is becoming widely accessible and is paramount in identifying novel disorders or atypical presentations. The pipelines are now robust enough to uncover substitutions, small indels and also those which are typically not elucidated by sequencing strategies like copy number changes, repeat expansions, etc. Methods: We present two clinical cases, one with a copy number variation and another with a triplet repeat expansion, both of which were missed on the exome sequencing and fragment analysis, respectively, and eventually were diagnosed with Whole Genome Sequencing. Results: Whole Genome Sequencing may not be the primary test of choice in either case. However when limited panel tests fail despite being sensitive and specific, it might lead to unnecessary broader-spectrum testing and distress. Therefore, it is worth looking into the possibility of common errors before ordering expensive and extensive tests. Rechecking the previous data in clinical cases with classic presentations and strong family history may be cumbersome, but it is a valuable exercise before proceeding with the chase for rarer and novel genetic disorders.