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

Abstract

Background: Next-generation sequencing has become a first-line tool for the diagnosis of primary immunodeficiency. However, patient access remains limited because of restricted insurance coverage and a lack of guidelines addressing the use of targeted panels versus whole-exome sequencing (WES).

Objectives: We sought to compare targeted next-generation sequencing with WES in a global population of patients with primary immunodeficiency.

Methods: This was a longitudinal study of 878 patients with likely primary immunodeficiency sequenced between 2010 and 2020. Most 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 to $950 with a WES-only approach, depending on diagnostic yield.

Conclusions: Advantages of WES over targeted next-generation sequencing include simplified workflow, reduced overall cost, and the potential for identification of novel diseases.

Keywords: Next-generation sequencing; genomics; primary immunodeficiency; targeted panel; whole-exome sequencing.

Fig 1.

A, B. NGS pipelines. Targeted NGS panel followed by WES (A) WES only (B). C. Overall diagnostic yield. Legend indicates variants meeting ACMG criteria for “pathogenic” or “likely pathogenic” mutation (pathogenic), VUS in genes that strongly fit the clinical phenotype (VUS), and published and non-published variants in novel genes at the time of sequencing.

Fig 2.

A. Mutation type (top panel) and inheritance pattern (bottom panel). B. Percent of patients in each IUIS disease category. C. Diagnostic yield in pediatric patients vs adults. D. Diagnostic yield in consanguineous vs non-consanguineous patients. E. Diagnostic yield based on features of clinical history.