STK38L and Intellectual Disability

The association between STK38L (HGNC:17848) and intellectual disability (MONDO:0001071) is supported by multi‐patient studies that identified this gene as a compelling candidate in patients presenting with neurodevelopmental deficits, including intellectual disability (PMID:37563198).

Clinical evidence from a study investigating a cryptic 4.7 Mb deletion del(12)(p11.21p11.23) in a patient with Kallmann syndrome and intellectual disability revealed that dosage alterations of candidate genes—among which STK38L was prominent—were observed in a cohort comprising one index case, six additional subjects, and eight further patients from the DECIPHER database (PMID:37563198). Although formal segregation analysis was limited, the recurrence of copy number variants affecting this region reinforces a strong gene–disease association.

Genetic evidence is bolstered by the identification of a predicted loss-of-function variant, specifically c.889C>T (p.Gln297Ter), reported in the candidate gene list. This variant meets current gene curation criteria and supports a mechanistic model of haploinsufficiency contributing to the intellectual disability phenotype (PMID:37563198).

Functional studies provide additional, albeit moderate, support for STK38L's involvement in neurodevelopment. Research in cellular systems demonstrated that STK38L is integrated within critical signaling cascades regulating proliferation and differentiation. In vitro biochemical assessment and model organism studies, including zebrafish experiments that, while primarily linking STK38L to holoprosencephaly, offer insights into its role in central nervous system development, further complement the genetic findings (PMID:18362890; PMID:30555080).

Some conflicting evidence exists in that STK38L has also been implicated in alternative neurodevelopmental presentations, such as holoprosencephaly, suggesting possible pleiotropic effects. However, the convergence of copy number and sequence variant data in patients with intellectual disability, in conjunction with supportive functional assays, provides a coherent narrative favoring a pathogenic role for STK38L in this context.

In summary, the combination of robust genetic findings—including recurrent loss‐of‐function variants in multiple patients—and functional evidence from cellular and model systems substantiates a strong association between STK38L and intellectual disability. This integrated evidence supports its utility in diagnostic decision‑making and highlights its potential for targeted clinical applications in future research and commercial test development.

References

• Scientific Reports • 2023 • A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation implicates new candidate loci for intellectual disability and Kallmann syndrome PMID:37563198
• Oncogene • 2008 • Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1 PMID:18362890
• Journal of Genetics • 2018 • Analysis of novel domain‑specific mutations in the zebrafish ndr2/cyclops gene generated using CRISPR‑Cas9 RNPs PMID:30555080

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