NF1 germline and somatic mosaicism

Abstract

NF1 affects ~1/3,000 individuals, irrespective of gender or ethnic background, and as many as 30-50 % of these patients present as sporadic or founder patients. A small fraction of these sporadic patients present with mosaicism for a first hit NF1 mutation. The precise frequency of mosaicism in NF1 is unknown, but first estimates indicate it may affect ~10 % of the patients with a total gene deletion. Here, we provide an overview of the different forms of mosaicism: gonadal or germline mosaicism, gonosomal mosaicism affecting both gonads and somatic cells, and somatic mosaicism, which may be generalized in phenotypic appearance or localized with a segmental distribution. Revertant mosaicism is discussed as well, though it has not yet been demonstrated in NF1 patients. Molecular data reported in the literature, proving the presence of an NF1 first hit mutation affecting only a portion of the body cells, depending on the timing of the mutational first hit during development, are summarized and the mutational spectrum and phenotype identified in mosaic NF1 patients are reviewed. The implications of our current understanding of mosaicism for molecular diagnostics in NF1 are discussed.