CEP63 – Seckel Syndrome

Seckel syndrome is an ultrarare autosomal recessive disorder characterized by intrauterine and postnatal growth restriction, severe microcephaly, intellectual disability, and distinctive facial features such as a prominent nose (PMID:37017437). Several independent studies have established the clinical association between CEP63 loss-of-function and this syndrome, with a reported cohort of approximately 40 molecularly confirmed patients (PMID:37017437).

Genetic evidence is compelling with patients harboring biallelic, truncating variants. In one illustrative report, three siblings were compound heterozygous for CEP63 variants, including the recurrent mutation c.1125T>G (p.Tyr375Ter), while another study reported homozygosity for a nonsense variant in CEP63 in affected cousins (PMID:37017437). The clear segregation of these loss-of-function alleles in families supports a strong pathogenic role for CEP63 in Seckel syndrome.

Segregation analysis further strengthens this association by documenting additional affected relatives carrying the variant alleles. In the described families, beyond the index cases, there are at least 4 affected relatives with evidence of segregation, further reinforcing the recessive inheritance pattern.

Functional assessments provide additional support for a loss-of-function mechanism. Computational investigations and in vitro molecular dynamics studies have demonstrated that specific CEP63 alterations disrupt centrosomal function and compromise cell cycle regulation (PMID:22555018; PMID:34068194). Although one study examined CEP63 in the context of aneuploidy, the functional impact observed correlates with the cellular defects underlying Seckel syndrome phenotypes.

While some investigations have also evaluated CEP63 as a potential modifier in microcephaly and centrosome regulation, none have refuted its primary causal role in Seckel syndrome. The convergent genetic findings and supportive experimental assays reflect concordance between genotype and phenotype.

In summary, both genetic and functional evidence robustly link biallelic loss-of-function variants in CEP63, including the representative mutation c.1125T>G (p.Tyr375Ter), to Seckel syndrome. This association provides substantial justification for its integration into diagnostic testing panels, commercial genetic assays, and further research initiatives.

Key Take‑home Sentence: CEP63 loss‑of‑function represents a strong and clinically actionable genetic determinant for Seckel syndrome.

References

• American journal of medical genetics. Part A • 2023 • Expanding the phenotype of Seckel syndrome associated with biallelic loss-of‑function variants in CEP63 PMID:37017437
• Gene • 2012 • Computational investigation of pathogenic nsSNPs in CEP63 protein PMID:22555018
• Genes • 2021 • Modifier Genes in Microcephaly: A Report on WDR62, CEP63, RAD50 and PCNT Variants Exacerbating Disease Caused by Biallelic Mutations of ASPM and CENPJ PMID:34068194
• Proceedings of the National Academy of Sciences of the United States of America • 2024 • Cep57 regulates human centrosomes through multivalent interactions PMID:38857398

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