We have identified a Coffin-Lowry syndrome pedigree where the disorder is associated with a novel splice site mutation in the RSK2 gene, leading to in-phase skipping of exon 5. Western blot analysis, using an antibody directed against the C-terminus of RSK2, failed to reveal RSK2 in this patient, suggesting strongly that the resulting internally deleted protein is unstable. The mutation was present in the DNA of one affected son and one manifesting daughter but was absent in two asymptomatic daughters, who carry the at-risk haplotype, and in the mother's somatic cell (lymphocyte) DNA. The results are consistent with the mutation arising as a postzygotic event in the mother, who therefore is a germinal mosaic. The application of linked markers to identify the disease allele for conventional genetic counselling would have been misleading in this family. This observation again highlights the importance of precise identification of the disease-causing mutation.