Null phenotype of neurofibromatosis type 1 in a carrier of a heterozygous atypical NF1 deletion due to mosaicism.

We coincidently detected an atypical deletion of at least 1.3-Mb encompassing the NF1 tumor suppressor gene and several adjacent genes at an apparent heterozygous level in blood of a 65 years old female patient. She had multiple subcutaneous tumors which appeared with certain similarity of subcutaneous neurofibromas which however revealed as lipomas by histological examination. Comprehensive and exhaustive clinical and radiological examinations did not detect any neurofibromatosis type 1-related clinical symptoms in the patient. Multiplex ligation-dependent probe amplification detected no or only very low level of the 1.3-Mb NF1 deletion in 6 lipomas and 2 skin biopsies. Digital PCR estimated the proportion of cells carrying a heterozygous NF1 deletion as 87% in the blood, and 8%, 10%, 13%, 17% and 20%, respectively, in the 5 lipomas investigated by this method, confirming our hypothesis of mosaicism. Our findings suggest that de novo cases of a genetic disease are potentially mosaic regardless of finding the mutation at an apparently heterozygous level in the blood, and that the possibility of mosaicism should be considered in genotype-phenotype studies and genetic counselling. This article is protected by copyright. All rights reserved.