Neurofibromatosis type I (NF1) microdeletion syndrome, accounting for 5–11% of NF1 patients, is caused by the heterozygous deletion ofNF1and a variable number of flanking genes in the 17q11.2 region. This syndrome is characterized by more severe symptoms than those shown by patients with intragenicNF1mutation and by variable expressivity, which is not fully explained by the haploinsufficiency of the genes included in the deletions. We here reevaluate an 8-year-old NF1 patient, who carries an atypical deletion generating theRNF135-SUZ12chimeric gene, previously described when he was 3 years old. As the patient has developed multiple cutaneous/subcutaneous neurofibromas over the past 5 years, we hypothesized a role ofRNF135-SUZ12chimeric gene in the onset of the patient’s tumor phenotype. Interestingly,SUZ12is generally lost or disrupted in NF1 microdeletion syndrome and frequently associated to cancer asRNF135.Expression analysis confirmed the presence of the chimeric gene transcript and revealed hypo-expression of five out of the seven analyzed target genes of the polycomb repressive complex 2 (PRC2), to which SUZ12 belongs, in the patient’s peripheral blood, indicating a higher transcriptional repression activity mediated by PRC2. Furthermore, decreased expression of tumor suppressor geneTP53, which is targeted by RNF135, was detected. These results suggest that RNF135-SUZ12 chimera may acquire a gain of function, compared with SUZ12 wild type in the PRC2 complex, and a loss of function relative to RNF135 wild type. Both events may have a role in the early onset of the patient’s neurofibromas.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10048-023-00718-8.