Evaluating clinical factors for improved utilization of targeted gene panel testing for inborn errors of immunity in a U.S. tertiary care pediatric hospital

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RationaleThere has been an increased use of targeted gene panels to evaluate inborn errors of immunity (IEI) due to increased availability and reduced costs. Refinements to clinical indications for targeted gene panels may improve yields for the test. MethodA retrospective chart review on 140 patients aged ≤18 years old with suspected IEI who had clinical targeted gene panel testing (Invitae®) for primary immune deficiency at a tertiary pediatric hospital in the U.S. Relevant clinical information and basic immunology labs, consisting of complete blood count, immunoglobulins, vaccine titers, immune competence, and other relevant lab tests, were evaluated. Additional patients with targeted gene panels sent over the course of 5 years are being reviewed to confirm these initial findings. ResultOf 140 patients (median age 3.9 years [IQR 1.6–9.5], 62% male, 85% Caucasian suspected of IEI and had the targeted gene panel sent, 9% had positive findings that led to a change in diagnosis and/or treatment plan. The most common indications for IEI workups in our cohort were infections (37%), organ-specific inflammation (30%), and periodic fevers (17%), Table 1. Of 52 patients with infections, 3 had pathogenic, or likely pathogenic variants in TNFRSF13B, CD40LG, and XLA genes. All patients with infections and normal clinical-based immunology testing had negative gene panels. Only one patient with organ-specific inflammation had a variant in STAT3 explaining her clinical features. Of 10 patients presenting with systemic autoimmune disease or polyautoimmunity, 5 had positive findings (STAT5B, TNFAIP3, NLRP12, COPA, and NLRC4 genes). Two of 24 patients with periodic fevers had variants in TNFAIP3 and MEFV, one had elevated inflammatory markers and one had positive family history. Of 9 patients who had WES after negative genetic panel, one patient had positive finding that explains his syndromic manifestations (PTEN).Table 1Primary Indication of sending targeted IEI panel and resultsPrimary Indications of sending targeted IEI gene panel N = 140)Number of patients with positive genetic testing that led to changes in diagnosis and/or treatment plans (n(%))Affected genes (each with n = 1)Infections (n = 52, 37%)3(6%)TNFRSF13B CD40LG XLAOrgan-specific inflammation (n = 42, 30%)1(2%)STAT3 LOF• Skin lesion (14)• Inflammatory bowel disease (9)• Cytopenias including ITP, Evan'ssyndrome and HLH (7)• Lymphadenopathy (3)• Others: enteropathy (3), pericarditis(2), arthritis (1), autoimmune hepatitis(1), endocrinologic disease (1), SNHL(1)Periodic fevers (n = 24,17%)2(8%)TNFAIP3 MEFVAbnormal newborn screening or1(9%)ATMabnormal immunology labs (n = 11, 8%)• Abnormal SCID screen (4)• Abnormal immunology labs (7)Systemic autoimmune disease or5 (50%)STAT5Bpolyautoimmunity (n = 10, 7%)TNFAIP3• Systemic autoimmune disease (4)NLRP12• Polyautoimmunity (6)COPANLRC4Family history (n = 1,1%)1 (100%)ATM• Pathogenic variant in ATMgene in identical twinIEI, inborn error of immunity; ITP, immune thrombocytopenia; HLH, hemophagocytic lymphohistiocytosis; SNHL, sensorineural hearing loss; SCID, severe combined immunodeficiency. ConclusionTargeted gene panel testing has the highest yield in patients with polyautoimmunity. Low yields of targeted gene panel were found in organ-specific inflammation, infections with normal clinical testing, and periodic fevers with normal inflammatory markers and a negative family history of IEI. Limitations included potentially missed cases from chart review.