The Diagnostic Yield of Exome Sequencing in Predominantly Antibody Deficient Patients Followed in Private Practice Allergy/Immunology Clinics

Predominantly Antibody Deficiencies (PAD) account for most inborn errors of immunity (IEI) followed in private practice Allergy/Immunology clinics. While the genetic revolution has provided significant insights to understand the molecular basis of many IEI disorders, genetic testing in PAD has yielded a molecular diagnosis in only 15–30% of patients. These numbers may however be inflated due to selection bias inherent in these studies being performed in academic referral clinics where more complicated patients tend to be referred. The diagnostic yield and utility of broad-based genetic testing is largely unknown in the private practice setting. Ten Consortium of Independent Immunology Clinics (CIIC) sites that provide care for more than 4,000 IEI patients (most with PAD) participated. Providers at each clinic proposed patients for inclusion using a questionnaire that included clinical and lab data that were reviewed by a 5-member enrollment committee. Patients were scored based on several factors including family history, early age of onset, autoimmune features, etc. and stratified as follows: P1 (5–17 points), P2 (3–4 points), P3 (1–2 points), and P4 (No points). P1, P2, and P3 patients were enrolled and samples sent for exome sequencing, lymphocyte subset analysis, and B cell immunophenotyping. Of 226 patients screened, 198 were selected for enrollment, and 137 submitted samples (48 P1, 58 P2, and 31 P3). Sixty percent were female, mean age 50.7 years (range 8–87), 57.6% had B cell abnormalities (low B cells, low memory B cells, low switched memory B cells, etc.), and 34.8% had Tor NK cell abnormalities (low numbers, reversed CD4/CD8 ratio, etc.). Causative pathogenic variants were identified in 8% of the exomes and highly suspicious VUS were identified in another 5%, predominantly in patients with a P1 priority score. We show that the diagnostic yield of broad-based genetic testing in PAD patients followed in private practice Allergy/Immunology clinics is somewhat lower than that reported in academic referral clinics. Diagnostic yield can, however, be improved by scoring clinical and laboratory features to stratify patients prior to testing. Acknowledgement: Supported by grants from Green Cross Corporation, Shire/Takeda, Pharming Group N.V., and Soleo Health.