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Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome

Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy
UO Dermatologia e Venereologia, Asst Papa Giovanni XXIII, 24127 Bergamo, Italy
Department of Dermatology, Consorcio Hospital General Universitario de Valencia, 46014 Valencia, Spain
Institute of Clinical Sciences, Imperial College London, London W12 0NN, UK
MRC London Institute of Medical Sciences, Imperial College London, W12 0NN London, UK
Department of Pediatric Genetics, Marmara University Medical School, 34890 Istanbul, Turkey
Department of Pediatrics, Eastern Mediterranean University, Mersin 10 Cyprus, Turkey
Centre de Génétique Humaine, Institut de Pathologie et de Génétique, 6041 Charleroi (Gosselies), Belgium
Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, 20149 Milan, Italy
Department of Medical Biotechnology and Translational Medicine, University of Milan, 20133 Milan, Italy
Institute for Maternal and Child Health, Foundation IRCCS Burlo Garofolo Institute, 34137 Trieste, Italy
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(4), 1103;
Received: 28 February 2018 / Revised: 31 March 2018 / Accepted: 3 April 2018 / Published: 6 April 2018
(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)
PDF [13858 KB, uploaded 3 May 2018]


Biallelic mutations in RECQL4 gene, a caretaker of the genome, cause Rothmund-Thomson type-II syndrome (RTS-II) and confer increased cancer risk if they damage the helicase domain. We describe five families exemplifying clinical and allelic heterogeneity of RTS-II, and report the effect of pathogenic RECQL4 variants by in silico predictions and transcripts analyses. Complete phenotype of patients #39 and #42 whose affected siblings developed osteosarcoma correlates with their c.[1048_1049del], c.[1878+32_1878+55del] and c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Literature survey highlights enrichment of these variants affecting the helicase domain in patients with cancer outcome raising the issue of strict oncological surveillance. Conversely, patients #29 and #19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Finally, despite matching several criteria for RTS clinical diagnosis, patient #38 is heterozygous for c.2412_2414del; no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype. View Full-Text
Keywords: Rothmund-Thomson syndrome; RECQL4; clinical expressivity; transcript analysis; osteosarcoma outcome Rothmund-Thomson syndrome; RECQL4; clinical expressivity; transcript analysis; osteosarcoma outcome

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Colombo, E.A.; Locatelli, A.; Cubells Sánchez, L.; Romeo, S.; Elcioglu, N.H.; Maystadt, I.; Esteve Martínez, A.; Sironi, A.; Fontana, L.; Finelli, P.; Gervasini, C.; Pecile, V.; Larizza, L. Rothmund-Thomson Syndrome: Insights from New Patients on the Genetic Variability Underpinning Clinical Presentation and Cancer Outcome. Int. J. Mol. Sci. 2018, 19, 1103.

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