NF1 single and multi-exons copy number variations in neurofibromatosis type 1

Neurofibromatosis type 1 (nf1) is caused by dominant loss-of-function mutations of the tumor suppressor nf1 containing 57 constitutive coding exons. a huge number of different pathogenic nf1 alterations has been reported. the aim of the present study was to evaluate the usefulness of a multiplex ligation-dependent probe amplification (mlpa) approach in nf1 patients to detect single and multi-exon nf1 gene copy number variations. a genotype–phenotype correlation was then performed in nf1 patients carrying these types of genetic alterations. among 565 nf1 index cases from the french nf1 cohort, single and multi-exon deletions/duplications screening identified nf1 partial deletions/duplications in 22 patients (~4%) using mlpa analysis. eight single exon deletions, 11 multiple exons deletions, 1 complex rearrangement and 2 duplications were identified. all results were confirmed using a custom array-cgh. mlpa and custom array-cgh allowed the identification of rearrangements that were missed by cdna/dna sequencing or microsatellite analysis. we then performed a targeted next-generation sequencing of nf1 that allowed confirmation of all 22 rearrangements. no clear genotype–phenotype correlations were found for the most clinically significant disease features of nf1 in patients with single and multi-exons nf1 gene copy number changes.