Article|Articles in Press, 100836

Biallelic variants in CRIPT cause a Rothmund-Thomson-like syndrome with increased cellular senescence

Published:March 31, 2023DOI:
      This paper is only available as a PDF. To read, Please Download here.



      Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the two known disease genes associated with RTS in over 70% of cases. We describe RTS-like features in five individuals with biallelic variants in CRIPT (OMIM#615789).


      Two newly identified and four published individuals with CRIPT variants were systematically compared to RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts.


      All CRIPT individuals fulfilled the diagnostic criteria for RTS, and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with RTS individuals. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors, and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate.


      CRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.

      Graphical abstract

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      ACMG Member Login

      Are you an ACMG Member? Sign in for online access.


      Subscribe to Genetics in Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect