Mosaic neurofibromatosis type 1 (NF1) poses a significant diagnostic challenge due to low-level mosaicism and the confinement of pathogenic variants to neuroectodermal lineages, frequently resulting in false-negative findings when testing is limited to peripheral blood. At present, molecular confirmation of NF1 often relies on the detection of pathogenic variants in tumour tissue. However, many young individuals present exclusively with benign pigmentary manifestations, such as café-au-lait macules and freckling, and therefore lack accessible tumour material. Molecular analysis of pigmentary lesions is technically challenging because skin biopsies contain only a small proportion of melanocytes, which particularly hampers the detection of low-level copy number and structural variants using conventional diagnostic approaches. We report a young woman referred for reproductive counselling who presented with unilateral pigmentary lesions suggestive of mosaic NF1, in whom a combined approach using melanocyte culture and optical genome mapping identified a reciprocal balanced translocation disrupting the NF1 locus, t(15;17)(q26.1;q11.2), representing the molecular predisposing event. To our knowledge, this is the first report of a reciprocal translocation in mosaic NF1, highlighting the role of structural genomic rearrangements in this disorder and underscoring the diagnostic utility of optical genome mapping in suspected cases. Molecular confirmation of mosaic NF1 is critical for accurate diagnosis, clinical management, and genetic counselling.
Blancke et al. (Sun,) studied this question.