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

Purpose: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789). Methods: Two newly identified and 4 published individuals with CRIPT variants were sys-tematically compared with those with RTS using clinical data, computational analysis of pho-tographs, 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 in-dividuals showed greatest facial similarity with individuals with RTS. 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. & COPY; 2023 by American College of Medical Genetics and Genomics. Published by Elsevier Inc.

Automated summary

This study identifies CRIPT gene mutations as being associated with features similar to Rothmund-Thomson syndrome (RTS). The individuals with CRIPT mutations not only exhibit symptoms of RTS, but also have neurodevelopmental delay and seizures. At a cellular level, both CRIPT and RTS mutations lead to increased cellular senescence, suggesting shared molecular mechanisms underlying the clinical phenotypes of these two diseases.