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Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1


Neurofibromatosis type 1 (NF1), an autosomal dominant disorder characterized by skin pigmentary lesions and multiple cutaneous neurofibromas, is caused by neurofibromin 1 (NF1) loss of function variants. Currently, a molecular diagnosis is frequently established using a multistep protocol based on cDNA and gDNA sequence analysis and/or Multiplex Ligation-dependent Probe Amplification (MLPA) assay on genomic DNA, providing an overall detection rate of about 95–97%. The small proportion of clinically diagnosed patients, which at present do not obtain a molecular confirmation likely are mosaic, as their pathogenic variant may remain undetected due to low sensitivity of low coverage NGS approaches, or they may carry a type of pathogenic variant refractory to currently used technologies. Here, we report two unrelated patients presenting with two different inversions that disrupt the NF1 coding sequence, resulting in an NF1 phenotype. In one subject, the inversion was associated with microdeletions spanning a few NF1 exons at both breakpoints, while in the other the rearrangement did not cause exon loss, thus testing negative by MLPA assay. Considering the high proportion of repeated regions within the NF1 sequence, we propose that intragenic structural rearrangements should be considered as possible pathogenic mechanisms in patients fulfilling the NIH diagnostic criteria of NF1 but lacking of molecular confirmation and in patients with NF1 intragenic microdeletions.

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Fig. 1: Genomic results on patient 1.
Fig. 2: OGM analysis disclosing the presence of a 499 Kb inversion disrupting NF1 gene.

Data availability

Data generated during this study have been submitted in ClinVar (ID SUB11349933, SUB11349931).


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Correspondence to Viola Alesi.

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The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institution’s Human Research Committee.

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Alesi, V., Lepri, F.R., Dentici, M.L. et al. Intragenic inversions in NF1 gene as pathogenic mechanism in neurofibromatosis type 1. Eur J Hum Genet (2022).

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