title: High rate of mosaicism in individuals with Cornelia de Lange syndrome.
abstract: BACKGROUND
  Cornelia de Lange syndrome (CdLS) is a well known malformation syndrome for which five causative genes are known, accounting for ∼55-65% of cases. In this study, we hypothesised that mosaicism might explain some of the ∼35-45% of cases without detectable mutation in DNA derived from lymphocytes; we investigated the frequency of NIPBL mutations in buccal cells in individuals negative for mutations in any of the five genes in lymphocytes; and we evaluated the efficiency of obtaining DNA from buccal swabs and the best strategy for optimal mutation detection in CdLS.
  
  
  METHODS
  Buccal swabs were obtained from eight mutation positive and 13 mutation negative individuals with clinically diagnosed CdLS, following informed consent. We then forwarded instructions and a single mouth swab to the families; if subsequently insufficient DNA was obtained, we re-sent two mouth swabs. Buccal cells were screened for NIPBL mutations using Sanger sequencing techniques.
  
  
  RESULTS
  Sufficient DNA for analysis was obtained in 21/22 individuals. In all six tested individuals with a known NIPBL mutation and in two with a known SMC1A mutation, the mutation was confirmed in buccal cells. In 10 of the 13 tested individuals without detectable mutation in lymphocytes a NIPBL mutation could be detected in buccal cells. Clinically there were no significant differences between patients with a germline and mosaic NIPBL mutation.
  
  
  CONCLUSIONS
  Somatic mosaicism for an NIPBL mutation is frequent (10/44; 23%) clinically in reliably diagnosed CdLS individuals. Obtaining buccal swabs at the time a blood sample is obtained will facilitate adequate molecular analysis of clinically diagnosed CdLS patients.
authors.affiliation: Department of Pediatrics, Room H7-237, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
authors.forename: Sylvia A
authors.initials: SA
authors.lastname: Huisman
authors.forename: Egbert J W
authors.initials: EJ
authors.lastname: Redeker
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Maas
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D003635:De Lange Syndrome / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009030:Mosaicism; D009061:Mouth Mucosa / Q000166:cytology; D011506:Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D000098550:Structural Maintenance of Chromosome Protein 1
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C487465:NIPBL protein, human; D011506:Proteins; D000098550:Structural Maintenance of Chromosome Protein 1