Mosaicism in Lowe syndrome

Abstract

In many X-linked and autosomal disorders, the absence of a mutation in the parents of an isolated affected child with a known mutation is still compatible with a significant recurrence risk because of parental mosaicism. Mosaicism has always been a theoretical possibility in Lowe Syndrome but has not been demonstrated to date. Proband LS-54, an isolated patient with Lowe syndrome, is hemizygous for a C→T transition in exon 18 which converts arginine to a stop at position 678 of the OCRL1 gene. The mutation is readily detectable because it creates an additional Ddel site within exon 18. Analysis of his mother's DNA obtained from peripheral blood leukocytes (PBL) revealed no mutation. Surprisingly, however, slit lamp examination of her lens by two independent observers revealed numerous micropunctate opacities distributed in a pattern characteristic of the carrier state for Lowe syndrome. Mutation analysis repeated on fresh samples of PBL DNA from the proband and his mother as well as on buccal scraping (BS) DNA from his mother confirmed the R678X mutation in the proband and its absence in DNA from both PBL and BS DNA in his mother. We interpret these results as indicating the mother is a likely somatic and germline mosaic for the mutation. Genetic counseling for Lowe Syndrome must take mosaicism into account when a DNA sample from the mother of an isolated case fails to demonstrate the mutation seen in an affected child.