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Recent evidence has identified STK38L (HGNC:17848) as a candidate gene in the etiology of Kallmann syndrome (MONDO_0018800). In a multi‐patient study of individuals with Kallmann syndrome and intellectual disability, two heterozygous point mutations in STK38L were detected, suggesting that dosage alterations of this gene may contribute to the combined phenotype (PMID:37563198). Although the number of unrelated probands is limited, the detection of a truncating variant, c.889C>T (p.Gln297Ter), provides preliminary genetic evidence supporting a role for STK38L in this disorder.
The genetic evidence is further underpinned by the identification of a second STK38L variant, c.546A>C (p.Lys182Asn), in affected individuals, which expands the variant spectrum to include both loss‑of‑function and missense events. However, due to the small number of observed cases and the absence of extensive familial segregation data, the overall gene-disease association remains limited at this stage.
Functional studies, although not disease‑specific, have demonstrated that STK38L plays important roles in cellular signaling pathways. For instance, biochemical assays have shown that STK38L interacts with key regulators such as MOB1 and contributes to phosphorylation cascades that are potentially relevant to neurodevelopment (PMID:18362890). These studies provide moderate functional evidence, suggesting that disruptions in STK38L function could plausibly impact pathways involved in the development of Kallmann syndrome.
No significant segregation data have been reported, and additional affected relatives with segregating variants are currently lacking. Nonetheless, the integration of the genetic data with supportive experimental findings from cellular models strengthens the tentative association, despite the acknowledged limitations regarding family-based evidence.
While the current body of evidence does not exceed the maximum ClinGen scoring thresholds, it sets the foundation for further research. Future studies involving larger cohorts, extended segregation analyses, and dedicated functional assays in neuronal contexts are warranted to clarify the role of STK38L in Kallmann syndrome.
Key take‑home: Although preliminary, the combined genetic and functional data highlight STK38L as a potential contributor to Kallmann syndrome, meriting further investigation for clinical diagnostic applications.
Gene–Disease AssociationLimitedOnly two point mutations in STK38L have been reported in individuals with Kallmann syndrome and intellectual disability (PMID:37563198), with no additional segregation evidence. Genetic EvidenceLimitedThe limited genetic evidence is based on two identified variants in STK38L (c.889C>T and c.546A>C) in affected individuals, which supports a preliminary association but lacks extensive replication or segregation data. Functional EvidenceModerateBiochemical studies demonstrate that STK38L is involved in critical phosphorylation cascades via its interaction with MOB1, underscoring its biological relevance, though direct links to Kallmann syndrome remain to be fully validated (PMID:18362890). |