STN1 – Coats plus syndrome

The telomere‐binding protein STN1 is implicated in autosomal recessive Coats plus syndrome through compound heterozygous loss-of-function and missense variants that disrupt CST complex function and telomere maintenance.

Clinical validity

The association of STN1 with Coats plus syndrome is classified as Moderate. Three unrelated patients have been described with biallelic STN1 variants leading to classical CP features (3 probands) (PMID:32627942; PMID:34110109; PMID:39539839). While no additional family segregation has been reported, the variants are absent from major population databases and fit a recessive loss-of-function model.

Genetic evidence

Coats plus syndrome follows autosomal recessive inheritance. Three case-level studies report four compound heterozygous STN1 variants: two truncating alleles (c.397C>T (p.Arg133Ter); c.894dup (p.Asp299ArgfsTer58)) and two missense alleles (c.985G>C (p.Ala329Pro); c.707T>C (p.Leu236Pro)). The novel missense variant c.985G>C (p.Ala329Pro) disrupts the STN1 C-terminal domain and is absent from ExAC, 1000 Genomes and gnomAD (PMID:32627942).

Functional evidence

Functional assays support a loss-of-function mechanism. Molecular dynamics simulations of p.Ala329Pro revealed impaired STN1-TEN1 interactions and domain destabilization (PMID:31245382). In vitro primase-Pol α stimulation assays demonstrate that STN1’s N-terminal OB-fold enhances POLA2 binding and DNA synthesis, whereas disease-causing mutations abolish these activities (PMID:28934486).

Phenotypic spectrum

Affected individuals display retinal exudates (HP:0001147), global developmental delay (HP:0001263), intracranial calcifications, gastrointestinal bleeding, and bone marrow failure. Ocular signs such as exotropia (HP:0000577) and cystoid macular edema are reported, with systemic bevacizumab showing transient benefit (PMID:39539839).

Integration & conclusion

Collectively, these genetic and experimental data establish STN1 as a gene for Coats plus syndrome, where biallelic LoF and destabilizing missense variants impair telomere capping. Genetic testing of STN1 is warranted in CP patients to confirm diagnosis, guide management, and enable accurate genetic counseling. Key Take-home: STN1 mutation analysis is clinically valuable for diagnosing Coats plus syndrome.

References

• American journal of medical genetics. Part A • 2020 • An Indian child with Coats plus syndrome due to mutations in STN1. PMID:32627942
• Molecular genetics & genomic medicine • 2021 • Novel compound heterozygous STN1 variants are associated with Coats Plus syndrome. PMID:34110109
• Journal of vitreoretinal diseases • 2024 • Improvement in Cystoid Macular Edema Secondary to Systemic Bevacizumab in a Patient With Coats Plus Syndrome. PMID:39539839
• Nucleic acids research • 2017 • STN1-POLA2 interaction provides a basis for primase-pol α stimulation by human STN1 PMID:28934486
• Frontiers in molecular biosciences • 2019 • Structural Analysis and Conformational Dynamics of STN1 Gene Mutations Involved in Coat Plus Syndrome. PMID:31245382

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