Rothmund–Thomson Syndrome: novel pathogenic mutations and frequencies of variants in the RECQL 4 and USB 1 (C16orf57) gene

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 RECQL 4 gene using PCR , SSCP ‐ PAGE analysis and/or Sanger sequencing. Patients with only one or no detectable mutation in the RECQL 4 gene were additionally tested for variants in the 8 exons of the USB 1 (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 RECQL 4 mutations including 10 novel and one homozygous novel USB 1 (C16orf57) mutation in a patient with PN . Moreover, we describe 31 RECQL 4 and 8 USB 1 sequence variants, four of them being novel intronic RECQL 4 sequence changes that may have some deleterious effects on splicing mechanisms and need further evaluation by transcript analyses. Conclusion 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.