Title: Approach to Identification of Patients with Activated Phosphoinositide-3 Kinase Delta Syndrome (APDS)

Authors: D. Suez 1, R. Wasserman 2, A. Darter 3, E. Perez 4, J. Jacobs 5, D. Siri 6, D. Patterson 7, J. Offenberger 8, W. Lumry 9, M. Scarupa 10 1. Daniel Suez MD, Allergy, Asthma & Immunology Clinic PA, Irving TX, 2. Allergy Partners of North Texas, Dallas, TX, 3. Oklahoma Institute of Allergy, Asthma & Immunology, Oklahoma City, OK, 4. Allergy Associates of the Palm Beaches PA, North Palm Beach, FL, 5. Allergy & Asthma Medical Group of the Bay Area, Inc., Brentwood, CA, 6. Midwest Allergy, Sinus, Asthma SC, Normal, IL, 7. Academy Allergy, Asthma & Sinus PC, Noblesville, IN, 8. Allergy & Asthma Relief Experts, Granada Hills, CA, 9. Allergy & Asthma Specialists of Dallas, Dallas, TX, 10. Institute for, Asthma, and Allergy, Wheaton, MD

Rational: APDS is a rare type of genetic Primary Immune Regulatory Disorder (PIRD) with symptoms that can vary widely among patients and appear similar to other PIRDs and Primary Immune Deficiency Disorders (PIDD), such that the only way to obtain a definitive diagnosis is through a genetic test. To improve the possibility to identify such patients we have developed an APDS screening Score Card to select patients for genetic diagnosis.

Methods: Six clinics of the Consortium of Independent Immunology Clinics (CIIC) participated in the study. 380 PID patients were screened using an APDS score card questioner, based on the most frequent clinical and laboratory findings in APDS including diagnostic criteria, infectious and non-infectious complications, flow cytometry and other laboratory data. Patients who scored 10 or above from a total of 30 points were selected for DNA Whole Exome Sequencing (WES) using an Invitae panel of 429 genes known to be associated with PID diseases.

Results: 117 out of 380 screened patients were selected and 75 were sampled for WES. Three patients were identified as harboring a heterozygous mutations in either of the APDS related genes (one PIK3R1 and two of PIK3CD), yet all three mutations were Variants with Unknown Significance (VUS). We have also identified 26 other PID pathological mutations and many other VUS variants which we will present at the meeting. Correlation between APDS screening score and the WES results will be presented as well.

Conclusions: Well Crafted Score Cards may help to select patients for genetic diagnosis.