CTC1 – Coats plus syndrome

Coats plus syndrome (MONDO:0012815) is a rare autosomal recessive telomere biology disorder characterized by bilateral exudative retinopathy, intracranial calcifications, leukoencephalopathy, osteopenia, gastrointestinal bleeding, and growth retardation. Mutations in the conserved telomere maintenance component 1 gene CTC1 (HGNC:26169) underlie this condition.

Initial whole-exome sequencing in four unrelated individuals with cerebroretinal microangiopathy with calcifications and cysts identified compound heterozygous CTC1 variants; subsequent Sanger sequencing revealed similar biallelic mutations in eight additional families, confirming autosomal recessive inheritance in at least 12 unrelated probands (PMID:22387016). Segregation analysis demonstrated that pathogenic CTC1 alleles co-segregate with disease across multiple families.

To date, over 70 distinct CTC1 variants—spanning missense, nonsense, frameshift, and splice-site changes—have been reported. A representative variant is c.1451A>C (p.His484Pro), identified in a patient with typical Coats plus features including dextrocardia (PMID:25928698). Recurrent alleles such as c.775G>A (p.Val259Met) have also been observed across diverse ancestries.

Functional studies have elucidated the mechanism of pathogenicity: frameshift mutants produce unstable truncated proteins that fail to assemble the CST complex, leading to progressive telomere shortening and fused chromosomes, while missense mutants impair STN1 interaction and DNA polymerase α recruitment (PMID:23869908). In vitro assays of CST function in patient cells reveal defective telomeric C-strand synthesis and excessive G-strand elongation by telomerase (PMID:24115768).

Patient-derived induced pluripotent stem cells (iPSCs) harboring biallelic CTC1 mutations exhibit telomere length heterogeneity, activation of alternative lengthening of telomeres (ALT), DNA damage accumulation mediated by γH2AX and 53BP1, and increased radiation sensitivity, faithfully modeling Coats plus pathology in vitro (PMID:36011306).

No studies have directly refuted the gene–disease relationship; the consistent genetic and experimental data across multiple cohorts and models support a definitive association. Genetic testing for CTC1 variants is critical for diagnosis, guiding surveillance for retinal, neurological, hematological, and gastrointestinal complications, and enabling carrier detection and genetic counseling.

Key Take‐home: Biallelic CTC1 mutation screening provides a definitive molecular diagnosis for Coats plus syndrome, facilitating targeted clinical management and familial risk assessment.

References

• American Journal of Human Genetics • 2012 • Mutations in CTC1, encoding the CTS telomere maintenance complex component 1, cause cerebroretinal microangiopathy with calcifications and cysts. PMID:22387016
• Aging Cell • 2013 • Functional characterization of human CTC1 mutations reveals novel mechanisms responsible for the pathogenesis of the telomere disease Coats plus. PMID:23869908
• Genes & Development • 2013 • Molecular basis of telomere syndrome caused by CTC1 mutations. PMID:24115768
• BMC Medical Genetics • 2015 • Whole exome sequencing in an Indian family links Coats plus syndrome and dextrocardia with a homozygous novel CTC1 and a rare HES7 variation. PMID:25928698
• Genes • 2022 • Patient-Derived iPSCs Reveal Evidence of Telomere Instability and DNA Repair Deficiency in Coats Plus Syndrome. PMID:36011306

Evidence Based Scoring (AI generated)