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This summary evaluates the association between IDO2 (HGNC:27269) and sarcoidosis (MONDO_0019338). In a recent whole exome sequencing study of three pediatric cases with sarcoidosis, rare recessively inherited variants in IDO2 were identified in each of the three trios (PMID:29510755). Despite the small number of probands (3 PMID:29510755), the segregation pattern – with affected children harboring variants while their healthy parents did not – supports an autosomal recessive inheritance model.
The genetic evidence includes the identification of coding changes in IDO2 that segregate in multiple families. One representative variant in IDO2 is reported as c.1077A>T (p.Tyr359Ter), which is consistent with a loss‑of‑function mechanism. Although the total number of affected individuals and additional segregating relatives is limited, the pattern across independent familial trios provides preliminary support for a gene‑disease association.
Functional studies have further investigated the impact of IDO2 variants on protein function. Two independent assessments showed that function‐altering polymorphisms in IDO2, including those leading to premature stop codons (e.g., Y359stop) and missense changes (e.g., R248W, converted to p.Arg248Trp when expressed in three‑letter amino acid codes), modify enzymatic activity and alter downstream immune responses (PMID:22754762; PMID:19476837). These data provide biochemical plausibility linking the genetic findings to the immune dysregulation seen in sarcoidosis, despite the functional assessments originating primarily from contexts outside sarcoidosis.
No conflicting evidence was reported from the studies reviewed, although the overall genetic support comes from a single collaborative study with a limited number of probands. The experimental findings, however, consistently show that reduced or abrogated IDO2 activity correlates with altered immune profiles. This integrated evidence suggests that IDO2 variants may contribute to sarcoidosis pathogenesis through loss‑of‑function mechanisms under a recessive model.
In conclusion, while the genetic evidence remains limited by the small sample size, the combination of familial segregation data and supportive functional assays provides a basis for further investigations. Future studies, including larger cohorts and targeted functional analyses in sarcoidosis models, are warranted.
Key Take‑home sentence: IDO2, through recessively inherited loss‑of‑function alleles, emerges as a promising candidate gene in the pathogenesis of pediatric sarcoidosis, meriting further validation for diagnostic and therapeutic applications.
Gene–Disease AssociationLimitedAssociation based on identification of recessively inherited variants in 3 pediatric probands (PMID:29510755); additional segregation evidence is limited. Genetic EvidenceLimitedGenetic evidence derives from a single study of 3 trios with autosomal recessive segregation, with one representative coding variant reported. Functional EvidenceModerateMultiple functional studies demonstrate that IDO2 polymorphisms alter enzymatic activity and immune responses (PMID:22754762; PMID:19476837), supporting biological plausibility. |