Mitotic recombination mediated by the JJAZF1 (KIAA0160) gene causing somatic mosaicism and a new type of constitutional NF1 microdeletion in two children of a mosaic female with only few manifestations

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an estimated birth incidence of 1 in 2500 and marked variability of expression. The hallmark symptoms of the fully manifested disease encountered in nearly all patients are cutaneous neurofibromas, cafe au lait spots, axillary freckling, and Lisch nodules. Other common manifestations are bone dysplasias, scoliosis, vasculopathy, and learning disabilities. NF1 patients also suffer from an increased risk of specific tumour types like plexiform neurofibromas, neurofibrosarcomas, optic gliomas, other CNS tumours, phaeochromocytomas, juvenile xanthogranuloma, and juvenile myeloid leukaemia. Mutations of the NF1 gene at 17q11.2 encoding neurofibromin are the molecular basis of the disease. Neurofibromin contains a GTPase activating domain and is a negative regulator of Ras GTPases. Homozygous inactivation of neurofibromin is associated with a dysregulation of Ras mediated signalling pathways and tumorigenesis in NF1 patients.1 More than 70% of the germline mutations are protein truncating and are distributed throughout the coding region.2–4 No distinct genotype-phenotype correlation concerning type and position of the mutations has been established, apart from patients with microdeletions of the NF1 gene region, which are associated with a more severe clinical phenotype and facial dysmorphism. This was recognised very early and confirmed by several studies.5–9 Molecular characterisation of the deletion boundaries showed that non-allelic recombination between two highly homologous sequences separated by ~1.5 Mb eliminates 14 genes together with the NF1 gene during germ cell development.10–14 These 60–85 kb spanning low copy repeats are derived from segments of the WI-12393 gene and contain sequences with homology to chromosome 19. The structure of the NF1 gene region at 17q11.2 is further complicated by other duplicated sequences, such as pseudogene exons of the SMURF2 and the KIAA0160 genes.10,15 Up to now, homologous recombination between these duplicated sequences during mitotic …