How Rare is Rare? TNFAIP3 Variants and the High Collective Burden of Haploinsufficiency

Predicted loss-of-function TNFAIP3 variants in human haploinsufficiency disease genes reach ~1:24,000 prevalence, and combined pLOF plus fHPPM reaches ~1:9,000.

• Why it matters: Monogenic immune disorders are often underdiagnosed because symptoms vary widely, leaving the true frequency and clinical impact of haploinsufficiency-linked variants unclear.
• What they did: The study screened loss-of-function–predicted TNFAIP3 variants in gnomAD, All of Us, and UK Biobank, then used PheWAS and PSEA for phenotype links, with TNFAIP3 follow-up in a University of Pittsburgh referral cohort and an MGB biobank.
• The result: Rare TNFAIP3 variants were linked to diverse immune phenotypes; in MGB, 29 individuals carried hypomorphic TNFAIP3 variants without HA20 diagnosis, with nearly two-thirds showing A20-hypomorphism–consistent features and only 4 receiving HA20-directed immunomodulatory therapy.

AI summary of the abstract · may contain errors · not medical advice · read the paper.