title: Rothmund-Thomson Syndrome: novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene.
abstract: BACKGROUND
  Poikiloderma is defined as a chronic skin condition presenting with a combination of punctate atrophy, areas of depigmentation, hyperpigmentation and telangiectasia. In a variety of hereditary syndromes such as Rothmund-Thomson syndrome (RTS), Clericuzio-type poikiloderma with neutropenia (PN) and Dyskeratosis Congenita (DC), poikiloderma occurs as one of the main symptoms. Here, we report on genotype and phenotype data of a cohort of 44 index patients with RTS or related genodermatoses.
  
  
  METHODS
  DNA samples from 43 patients were screened for variants in the 21 exons of the RECQL4 gene using PCR, SSCP-PAGE analysis and/or Sanger sequencing. Patients with only one or no detectable mutation in the RECQL4 gene were additionally tested for variants in the 8 exons of the USB1 (C16orf57) gene by Sanger sequencing. The effect of novel variants was evaluated by phylogenic studies, single-nucleotide polymorphism (SNP) databases and in silico analyses.
  
  
  RESULTS
  We identified 23 different RECQL4 mutations including 10 novel and one homozygous novel USB1 (C16orf57) mutation in a patient with PN. Moreover, we describe 31 RECQL4 and 8 USB1 sequence variants, four of them being novel intronic RECQL4 sequence changes that may have some deleterious effects on splicing mechanisms and need further evaluation by transcript analyses.
  
  
  CONCLUSIONS
  The current study contributes to the improvement of genetic diagnostic strategies and interpretation in RTS and PN that is relevant in order to assess the patients' cancer risk, to avoid continuous and inconclusive clinical evaluations and to clarify the recurrence risk in the families. Additionally, it shows that the phenotype of more than 50% of the patients with suspected Rothmund-Thomson disease may be due to mutations in other genes raising the need for further extended genetic analyses.
authors.affiliation: Division of Human GeneticsDepartment of PaediatricsInselspitalUniversity of BernCH-3010BernSwitzerland; Department of Clinical ResearchUniversity of BernCH-3010BernSwitzerland.
authors.forename: Aude-Annick
authors.initials: AA
authors.lastname: Suter
authors.affiliation: Department of Dermatology University of Basel Basel Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Itin
authors.affiliation: Medical Genetics University Hospital Basel Basel Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.affiliation: Wessex Clinical Genetics Service University Hospital Southampton Southampton UK.
authors.forename: Munaza
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Clinical Genetics Guys Hospital London UK.
authors.forename: Tazeen
authors.initials: T
authors.lastname: Ashraf
authors.affiliation: Department of Clinical Genetics Agia Sophia Children's Hospital Athens Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Fryssira
authors.affiliation: Department of Clinical Genetics Oxford University Hospitals NHS Trust Oxford UK.
authors.forename: Usha
authors.initials: U
authors.lastname: Kini
authors.affiliation: INGEMM, Institute of Medical and Molecular Genetics University Hospital La Paz, IdiPAZ-CIBERER Madrid Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.affiliation: Medical Genetics University Hospital Basel Basel Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Miny
authors.affiliation: Department of Dermatology Aarhus University Hospital Aarhus Denmark.
authors.forename: Mette
authors.initials: M
authors.lastname: Sommerlund
authors.affiliation: Departement of Clinical Genetics Nottingham University Hospitals NHS Trust City Hospital Campus Nottingham UK.
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.affiliation: Department of Clinical Genetics Aarhus University Hospital Aarhus Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Vaeth
authors.affiliation: Department of Clinical Genetics University Hospitals of Leicester NHS Trust Leicester Royal Infirmary Leicester UK.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Vasudevan
authors.affiliation: Division of Human GeneticsDepartment of PaediatricsInselspitalUniversity of BernCH-3010BernSwitzerland; Department of Clinical ResearchUniversity of BernCH-3010BernSwitzerland.
authors.forename: Sabina
authors.initials: S
authors.lastname: Gallati
keywords: Poikiloderma with neutropenia; RECQL4 gene; Rothmund–Thomson Syndrome; USB1 (C16orf57) gene