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WRAP53 – Dyskeratosis congenita

Dyskeratosis congenita (DC) is a telomere biology disorder characterized by reticulated skin pigmentation, nail dystrophy and oral leukoplakia. DC results from impaired telomerase function leading to bone marrow failure and cancer predisposition.

Autosomal recessive DC arises from biallelic pathogenic variants in WRAP53, which encodes the telomerase Cajal body protein TCAB1. In a Chinese Han family, a homozygous c.892C>T (p.Arg298Trp) variant was identified in the proband, with both parents and an unaffected sibling as heterozygous carriers (PMID:29514627).

An unrelated DC patient harbored compound heterozygous missense variants including c.492C>A (p.Phe164Leu), establishing two probands with autosomal recessive inheritance and concordant phenotypes (PMID:21205863).

Functional assays demonstrate that WRAP53 mutations disrupt telomerase trafficking to Cajal bodies, mislocalize telomerase RNA to nucleoli and impair telomere elongation in patient-derived cells (PMID:21205863).

Mechanistic studies in Hoyeraal–Hreidarsson syndrome further show that variants such as p.Leu283Phe and p.Arg398Trp destabilize WRAP53, abolish Cajal body formation and compromise DNA double-strand break repair, confirming a loss-of-function mechanism (PMID:32303682).

No conflicting genetic evidence has been reported. The concordance of clinical, genetic and experimental data across two independent probands supports a strong gene–disease relationship.

Integration of these findings establishes autosomal recessive WRAP53 deficiency as a cause of DC via defective telomerase trafficking, informing diagnostic gene panels and guiding telomere-targeted therapeutic approaches.

References

  • Genes & development • 2011 • Disruption of telomerase trafficking by TCAB1 mutation causes dyskeratosis congenita. PMID:21205863
  • BMC medical genetics • 2018 • A unique homozygous WRAP53 Arg298Trp mutation underlies dyskeratosis congenita in a Chinese Han family PMID:29514627
  • Cell Death & Disease • 2020 • Biallelic mutations in WRAP53 result in dysfunctional telomeres, Cajal bodies and DNA repair, thereby causing Hoyeraal-Hreidarsson syndrome. PMID:32303682

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Two probands in independent families with biallelic WRAP53 variants and concordant functional data

Genetic Evidence

Moderate

Two unrelated probands with autosomal recessive biallelic variants including c.892C>T (p.Arg298Trp)(PMID:29514627) and c.492C>A (p.Phe164Leu)(PMID:21205863); limited segregation

Functional Evidence

Strong

Multiple in vitro studies show WRAP53 variants disrupt telomerase trafficking, Cajal body assembly and telomere elongation(PMID:21205863,PMID:32303682)