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Abstract
Purpose
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).
Methods
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.
Results
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.
Conclusion
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
Graphical Abstract
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Article info
Publication history
Accepted:
March 28,
2023
Received in revised form:
March 25,
2023
Received:
May 25,
2022
Publication stage
In Press Accepted ManuscriptFootnotes
Key messages:
(1) CRIPT causes a Rothmund-Thomson-like syndrome that is associated with developmental delay.
(2) Biallelic variants in CRIPT cause increased cellular senescence which is a shared cellular phenotype of CRIPT and RECQL4 deficiencies.
(3) In fibroblasts derived from individuals with pathogenic variants in CRIPT, mitotic progression and mitotic arrest induction are not compromised and the incidence of mitotic errors is not significantly increased.
(4) Fibroblasts from CRIPT and RECQL4 individuals show no or only very mild sensitivity to ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate compared to controls.
Identification
Copyright
© 2023 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.
