Enhanced clinical decision-making to optimize targeted gene panel testing for inborn errors of immunity

Targeted gene panels (TGPs) are frequently used to assess inborn errors of immunity (IEI) owing to the expanding knowledge of monogenic causes. Refining their clinical indications may enhance test yields.

To assess clinical factors associated with the diagnostic results of IEI from TGP in pediatrics.

A retrospective study of pediatric patients with suspected IEI who underwent Invitae TGP over a 5-year period at a tertiary hospital in the U.S.

Of the 350 patients (median age 5.1 years, IQR [1.6,10.9]; 56% male; 85% White), 8.3% had diagnostic genetic testing results (pathogenic, likely pathogenic, or variants of uncertain significance considered to be pathogenic). A genetic diagnosis of IEI from TGPs was more frequent in patients who had testing sent because of a positive severe combined immunodeficiency (SCID) newborn screen (odds ratio [OR] 10.21; 95% CI 3.26-31.92) and in patients with clinical diagnoses of combined immunodeficiency (OR 11.85; CI 4.23-33.17) or SCID (OR 51.2; CI 5.51-475.52). Patients who had immune dysregulation without infections, along with multiple autoimmunity (P <.001) and nonatopic skin lesions (P = .002), were more likely to have diagnostic TGP.

Genetic testing for IEI should be strongly considered in patients with a positive newborn SCID screen, clinical diagnoses of combined immunodeficiency or SCID, and immune dysregulation with multiple autoimmunity or nonatopic skin lesions.