Manager, Medical Affairs Baylor Genetics Richmond, Virginia, United States
Background: Whole genome sequencing (WGS) offers a comprehensive solution for genetic investigation by capturing a wide range of genomic variations in a single test. Conventional phenotype-driven and stepwise genetic testing is time-consuming and may yield inconclusive results. Moreover, the genetic investigation paradigm often stops at the point of identifying a single diagnosis, potentially overlooking additional underlying genetic etiologies. WGS is now often utilized as a first- or second-tier test for patients with multiple congenital anomalies (MCA), developmental delay and intellectual disability (DD/ID). Limited data exist on the frequency of patients receiving multiple genetic diagnoses pertaining to their phenotype. Objective: To understand the frequency, type, associated indication, and other characteristics of multiple genetic diagnoses made by WGS. Design/Methods: This is a retrospective evaluation of WGS results at Baylor Genetics. Demographic data, clinical history, diagnostic findings and the frequency of patients who had multiple reportable molecular findings were investigated. Results: Reportable multilocus findings were detected in 78 cases; including 1 case with triple diagnoses, 24 cases with dual molecular diagnoses (pathogenic or likely pathogenic variants); 36 cases with one diagnosis in conjunction with reportable finding(s) in another locus [2 variants in an autosomal recessive (AR) locus or 1 variant in an autosomal dominant (AD) locus]; 7 cases with one molecular diagnosis and one reportable variant in an AR locus; and 7 cases with one molecular diagnosis and an actionable secondary finding. Among the 24 cases with dual diagnoses, the most common clinical indications included MCA (n=21), DD/ID (n=7), seizures (n=3), and failure to thrive (n=4). Parental samples were available in 13 cases which revealed that de novo findings accounted for at least one of the diagnostic variants in 11 trios.
Conclusion(s): This study demonstrates the utility of WGS to provide reportable multilocus findings. This finding is significant not only in ending diagnostic odysseys but also in demonstrating the need to account for heterogenous variant types and multiple molecular etiologies associated with complex patient phenotypes. In addition, WGS can also aid in optimizing management and expediting diagnoses of critically ill patients in the NICU, PICU, and other settings with complex phenotypes. Multiple molecular diagnoses will also improve the understanding of rare diseases by better understanding the clinical effects of multiple variants at more than one locus.
