TY - JOUR
T1 - Biallelic variants in CRIPT cause a Rothmund-Thomson-like syndrome with increased cellular senescence
AU - Averdunk, Luisa
AU - Huetzen, Maxim A.
AU - Moreno-Andrés, Daniel
AU - Kalb, Reinhard
AU - McKee, Shane
AU - Hsieh, Tzung Chien
AU - Seibt, Annette
AU - Schouwink, Marten
AU - Lalani, Seema
AU - Faqeih, Eissa Ali
AU - Brunet, Theresa
AU - Boor, Peter
AU - Neveling, Kornelia
AU - Hoischen, Alexander
AU - Hildebrandt, Barbara
AU - Graf, Elisabeth
AU - Lu, Linchao
AU - Jin, Weidong
AU - Schaper, Joerg
AU - Omer, Jamal A.
AU - Demaret, Tanguy
AU - Fleischer, Nicole
AU - Schindler, Detlev
AU - Krawitz, Peter
AU - Mayatepek, Ertan
AU - Wieczorek, Dagmar
AU - Wang, Lisa L.
AU - Antonin, Wolfram
AU - Jachimowicz, Ron D.
AU - von Felbert, Verena
AU - Distelmaier, Felix
N1 - Publisher Copyright:
© 2023 American College of Medical Genetics and Genomics
PY - 2023/7
Y1 - 2023/7
N2 - 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 systematically compared with those with 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 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.
AB - 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 systematically compared with those with 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 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.
KW - Aging
KW - DNA damage and repair
KW - Mitotic errors
KW - Rothmund-Thomson syndrome
KW - Senescence
UR - http://www.scopus.com/inward/record.url?scp=85161357983&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2023.100836
DO - 10.1016/j.gim.2023.100836
M3 - Article
C2 - 37013901
AN - SCOPUS:85161357983
SN - 1098-3600
VL - 25
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 7
M1 - 100836
ER -