W147 - Estimated Prevalence and Clinical Manifestations of TNFAIP3 Variants Associated with Haploinsufficiency of A20 (HA20) in the United States

Prabal Chhibbar – University of Pittsburgh; Priyamvada Guha Roy – University of Pittsburgh; Jishnu Das – University of Pittsburgh; Daniella Schwartz – University of Pittsburgh

Abstract Text: TNFAIP3 encodes the regulatory protein A20, which is a potent inhibitor of multiple inflammatory signaling pathways. High-penetrance heterozygous germline mutations in TNFAIP3 cause early-onset immune dysregulation, recently described as the rare monogenic disease Haploinsufficiency of A20 (HA20). The prevalence of HA20 in the United States is likely underreported and limited by ascertainment biases. To determine the prevalence of pathogenic TNFAIP3 variants and associated clinical phenotypes, we used data from the All of Us Research Program, a multidisciplinary consortium that integrates electronic health records (EHR) and whole genome sequencing (WGS). Of 244,845 WGS participants (mean age, 58.6 years; 51.3% White; 59.3% female), 475 individuals harbored 101 TNFAIP3 variants with definitive pathogenicity (n=11; frameshift, nonsense, or splice site) or predicted pathogenicity (n=90; missense; CADD-Phred ≥ 25; SIFT=deleterious; PolyPhen=probably damaging; MAF < 0.01%). 87 participants (mean age, 58.1 years; 62.1% White; 52.9% female) with 31 high probability pathogenic variants (CADD-Phred ≥ 30; SIFT=deleterious; PolyPhen=probably damaging; MAF < 0.01%) were identified. In this group, inflammatory phenotypes (94.9%) were present in individuals with linked EHR data (n=59), including rash (44.1%), gastrointestinal inflammation (62.7%), arthritis/arthralgia (71.2%), neurologic complications (57.6%), vascular complications (52.5%), cytopenia (39.0%), infection (57.6%), genitourinary complications (44.1%), autoimmunity (37.3%), and psychiatric diagnosis (49.2%). The mean prevalence of high probability pathogenic variants was 1:2782 (95% CI, 1:2258-1:3427, Wilson/Brown). The mean prevalence of definitively pathogenic variants was 1:14403 (95% CI, 1:8993-1:23067, Wilson/Brown). This suggests that 14,400-148,000 Americans suffer from A20-insufficient disease. Studies are ongoing to functionally validate the high probability pathogenic TNFAIP3 missense variants.