Efficacy and economics of targeted panel versus whole exome sequencing in 878 patients with suspected primary immunodeficiency.

Abstract Background NGS has become a first-line tool for diagnosis of PID. However, patient access remains limited due to restricted insurance coverage and a lack of guidelines addressing use of targeted panels vs WES. Objectives To compare targeted next generation sequencing (NGS) with whole exome sequencing (WES) in a global population of patients with primary immunodeficiency (PID). Methods This is a longitudinal study of 878 patients with likely PID sequenced between 2010 and 2020. The majority of patients (n=780) were first sequenced using a 264 gene panel. This was followed by WES in selected cases if a candidate gene was not found. A subset of patients (n=98) were selected for a WES-only pipeline if the history was atypical for genes within the targeted panel. Results Disease-causing variants were identified in 498 of the 878 probands (56%), encompassing 152 distinct monogenic disorders. Sixteen patients had disorders that were novel at the time of sequencing (1.8%). Diagnostic yield in patients sequenced by targeted panel was 56% (433 of 780 patients) with subsequent WES leading to an additional 18 diagnoses (overall diagnostic yield 58%, 451 of 780 patients). The WES-only approach had a diagnostic yield of 45% (45 of 98 patients), reflecting that these cases had less common clinical and laboratory phenotypes. Cost analysis, based on current commercial WES and targeted panel prices, demonstrated savings ranging from $300-$950 with a WES-only approach, depending on diagnostic yield.