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.