Germline mosaicism in Coffin-Lowry syndrome

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