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The current evidence linking SPICE1 (HGNC:25083) with sarcoidosis (MONDO_0019338) is based on whole‐exome sequencing studies performed in three independent pediatric trios with sarcoidosis (PMID:29510755). In these studies, recessive variants were identified in a panel of 37 candidate genes, with SPICE1 emerging as one gene of interest that segregated with the disease in the affected probands. Given that only three probands have been reported and there is a lack of further experimental validation or extended segregation in additional relatives, the overall clinical validity is categorized as Limited. The genetic evidence is characterized by the detection of a candidate variant in SPICE1 that follows an autosomal recessive inheritance pattern with no additional affected relatives reported. No recurring founder variants or functional experiments specific to SPICE1 have yet been documented, which further limits the certainty of this association.
The functional assessment of SPICE1 in sarcoidosis remains preliminary with no detailed mechanistic studies or animal models provided. This leaves open questions regarding the exact mechanism of pathogenicity, though hypotheses include potential disruptions in intracellular trafficking and autophagy, processes implicated in granuloma formation. The absence of robust functional rescue or knock‑out experiments means that current functional evidence remains insufficient to elevate the association beyond the Limited range. Overall, while SPICE1 is a promising candidate gene for sarcoidosis based on recessive variant identification in pediatric cases, additional genetic replication and experimental validation are needed to support its clinical utility. Key take‑home: SPICE1 remains a candidate with putative involvement in sarcoidosis, underscoring the urgent need for further functional and replication studies.
Gene–Disease AssociationLimitedEvidence is based on three probands from independent trios segregating recessive SPICE1 variants (PMID:29510755), without further segregation or extensive experimental validation. Genetic EvidenceLimitedOnly one candidate SPICE1 variant was identified in three affected probands with autosomal recessive inheritance, lacking recurrence or additional corroborative reports. Functional EvidenceLimitedNo gene-specific functional assays, animal models, or rescue experiments have been reported; mechanistic insights remain speculative. |