Maternal de novo triple mosaicism for two single OCRL nucleotide substitutions (c.1736A>T, c.1736A>G) in a Lowe syndrome family

Since the identification of the Lowe's oculocerebrorenal syndrome gene, more than 100 distinct OCRL mutations have been observed. Germline mosaicism has rarely been detected in Lowe families; however, the presence of mosaic mutations, in particular triple mosaicism, may often remain undiagnosed. In the course of OCRL analysis in a Polish family, the index case showed a hemizygous nucleotide transition (c.1736A>G, p.His507Arg). Gene analysis in the patient's mother not only provided evidence that she is a carrier of the mutant allele transmitted to her son but also showed an additional c.1736A>T (p.His507Leu) transversion affecting the same base position. DNA from a mouthwash sample from the mother showed a similar fluorescence intensity pattern at the affected nucleotide. These data, together with the findings that maternal grandparents solely showed wildtype sequence, implied a de novo mosaicism in the mother. Triple X syndrome was ruled out by karyotype analysis and a partial or complete gene duplication could be excluded. Allele-specific amplification confirmed the results of three alleles being present in the mother. The amount of wildtype allele detected in qPCR implied the presence of cells solely harboring c.1736A and single-cell PCR experiments confirmed the presence of non-mutant cells in the mother's blood. These data suggest that the mutations observed are the result of two de novo events in early embryogenesis of the mother. To the best of our knowledge, this is the first observation of triple mosaicism at a single nucleotide.