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

Abstract

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 the blood of a 65‐year‐old female patient. She had multiple subcutaneous tumors that appeared with a certain similarity of subcutaneous neurofibromas, which, however, was 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 six lipomas and two skin biopsies. Digital polymerase chain reaction estimated the proportion of cells carrying a heterozygous NF1 deletion at 87% in the blood, and 8%, 10%, 13%, 17%, and 20%, respectively, in the five lipomas investigated by this method, confirming our hypothesis of mosaicism. Our findings suggest that de novo cases of 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 counseling.

Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth

“…We did not identify statistically significant differences in averaged annual growth of tumors between NF1 patients with type-1 deletions and those with atypical deletions. This might be expected, as atypical deletions often are heterozygous and associated with genetic mosaicism, which results in a variety of phenotypes of NF1, ranging from severe forms, similar to that of the type-1 deletion to mild forms, which are clinically almost indetectable[ 32 ]. However, due to the exclusion of patients with known or suspected genetic mosaicism in this study, phenotypical differences between type-1 deletions and atypical deletions might be limited in the investigated cohort.…”

“…All patients were screened for whole gene deletions using multiple intragenic microsatellite markers or directly with a multiple-ligation-dependent primer amplification assay [ 7 , 32 ] Patients without whole gene deletions were further screened for intragenic minor NF1 mutations by direct Sanger sequencing (Supporting information S1 and S2 Tables ) [ 33 ]. All patients included received clinical care and genetic counseling at our outpatient clinic.…”