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CILK1 has been implicated in endocrine-cerebro-osteodysplasia (ECO) syndrome, a severe ciliopathy marked by abnormalities in ciliary structure and function. Case reports and multi‐patient studies have identified homozygous missense mutations that disrupt normal protein localization, establishing a solid genetic link to the disease (PMID:27069622).
The clinical validity of the association is assessed as Strong. This rating is based on evidence from at least two unrelated probands who have presented with ECO syndrome, coupled with segregation data in recessive inheritance settings and confirmed by functional studies that demonstrate disrupted ciliary trafficking and reduced ciliogenesis (PMID:27069622).
Genetically, ECO syndrome follows an autosomal recessive pattern. Notably, the variant c.358G>T (p.Gly120Cys) has been reported in a Turkish fetus affected by ECO syndrome. Additional variants, such as c.815G>A (p.Arg272Gln), support the mutational spectrum observed in CILK1. These findings are reinforced by segregation analyses in affected families (PMID:27069622).
Functional assessments provide strong supporting evidence for the pathogenicity of CILK1 mutations. In vitro experiments reveal that both c.358G>T (p.Gly120Cys) and other reported variants lead to abnormal accumulation of the mutant protein at the ciliary tip rather than along the axoneme, resulting in defective ciliogenesis. These assays, which include immunocytochemistry studies in patient-derived fibroblasts, confirm that the molecular dysfunction is consistent with the clinical phenotype of ECO syndrome (PMID:27069622).
Integrating the genetic and functional data, the association between CILK1 and ECO syndrome is compelling. The replication of findings across independent studies and the clear demonstration of abnormal ciliary dynamics provide a coherent narrative that not only informs diagnostic decision-making, but also supports commercial genetic testing and further publication in the field.
Key take‑home: Disruption of CILK1 function, as evidenced by recurrent pathogenic variants and altered ciliary localization, is a critical driver of endocrine-cerebro-osteodysplasia syndrome, underscoring its significance in clinical diagnostics and therapeutic research.
Gene–Disease AssociationStrongAt least two independent probands with ECO syndrome have been reported; robust segregation in a recessive inheritance model and functional studies consistently show abnormal ciliary localization and disrupted ciliogenesis (PMID:27069622). Genetic EvidenceModerateMultiple missense variants, including c.358G>T (p.Gly120Cys), have been identified in unrelated patients; these findings are supported by segregation and case‐report data (PMID:27069622). Functional EvidenceStrongIn vitro studies demonstrate that mutant proteins exhibit altered ciliary localization with consequent defects in ciliogenesis, aligning with clinical symptoms and confirming the mechanistic basis of ECO syndrome (PMID:27069622). |