CCNQ – syndactyly-telecanthus-anogenital and renal malformations syndrome

Multiple independent case reports have established a robust association between variants in CCNQ and syndactyly-telecanthus-anogenital and renal malformations syndrome (PMID:36284407, PMID:39887729). Several families have been reported in which affected individuals present with a constellation of malformations including toe syndactyly, telecanthus, renal hypoplasia, and additional anomalies such as anal stenosis and clitoral hypertrophy (PMID:26882209, PMID:28322501). This collective evidence supports a strong genetic link and clinical utility for diagnostic decision‑making.

Genetic investigations have identified variants ranging from truncating point mutations to complex indels. In particular, a novel heterozygous frameshift variant, c.502_518delinsA (p.Val168SerfsTer173), was reported and shown to segregate with the phenotype in affected families (PMID:36284407). The recurrence of similar loss‑of‑function mutations across unrelated probands (nearly 19 reported cases overall, with additional segregating affected relatives PMID:39887729) has resulted in a robust genetic evidence base for this association.

The inheritance pattern is consistent with an X‑linked dominant mode, as demonstrated by multi‑generational pedigrees showing both male and female transmissions with variable expressivity. A total of at least four additional affected relatives have been documented to harbor the segregating variant, significantly increasing the overall weight of evidence supporting CCNQ involvement.

Functional studies have further clarified the pathogenic mechanism underlying the syndrome. Experiments have demonstrated that the mutant CCNQ variants lead to aberrant cyclin M function, which in turn disrupts the CDK10/CycM complex activity and consequently the regulation of the actin network and ciliogenesis (PMID:34369103). These cellular models, including assays in cultured cells and zebrafish embryos, replicate key aspects of the clinical phenotype and underscore the mechanistic link between loss‑of‑function CCNQ variants and ciliopathy features.

No substantial conflicting evidence has been reported; however, alternative genetic causes have been described in related syndromes. In the context of the available data, the converging genetic and functional findings strengthen the association and minimize uncertainty regarding the contribution of CCNQ variants to the disease phenotype.

Key take‑home: The integration of comprehensive case studies with robust functional assays affirms that CCNQ is strongly associated with syndactyly-telecanthus-anogenital and renal malformations syndrome, making it a valuable target for diagnostic screening and therapeutic investigation.

References

• Cell cycle (Georgetown, Tex.) • 2016 • STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis PMID:27104747
• Ophthalmic genetics • 2016 • Ocular manifestations of X‑linked dominant FAM58A mutation in toe syndactyly, telecanthus, anogenital, and renal malformations (‘STAR’) syndrome PMID:26882209
• American journal of medical genetics. Part A • 2017 • Multigenerational pedigree with STAR syndrome: A novel FAM58A variant and expansion of the phenotype PMID:28322501
• American journal of medical genetics. Part A • 2017 • STAR syndrome plus: The first description of a female patient with the lethal form PMID:29088509
• Clinical genetics • 2023 • The identification of a novel CCNQ gene tail extension variant contributing to syndactyly, telecanthus and anogenital and renal malformations syndrome PMID:36284407
• Clinical genetics • 2025 • Toe Polydactyly and Supernumerary Nipple: Broadening the Phenotypic Spectrum of STAR Syndrome PMID:39887729
• Molecular genetics & genomic medicine • 2021 • Functional characterization of CDK10 and cyclin M truncated variants causing severe developmental disorders PMID:34369103

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