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

Genetics in medicine : official journal of the American College of Medical Genetics

Authors: Luisa Averdunk, Maxim A Huetzen, Daniel Moreno-Andrés, Reinhard Kalb, Shane McKee, Tzung-Chien Hsieh, Annette Seibt, Marten Schouwink, Seema Lalani, Eissa Ali Faqeih, Theresa Brunet, Peter Boor, Kornelia Neveling, Alexander Hoischen, Barbara Hildebrandt, Elisabeth Graf, Linchao Lu, Weidong Jin, Joerg Schaper, Jamal A Omer, Tanguy Demaret, Nicole Fleischer, Detlev Schindler, Peter Krawitz, Ertan Mayatepek, Dagmar Wieczorek, Lisa L Wang, Wolfram Antonin, Ron D Jachimowicz, Verena von Felbert, Felix Distelmaier

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.

Copyright © 2023. Published by Elsevier Inc.

PMID: 37013901

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