Rare variants modulating phenotype in NF1 carriers

Neurofibromatosis type 1 (NF1) is a rare genetic disorder with highly variable phenotypes, ranging from psychosocial challenges and congenital malformations to benign tumors and even aggressive cancers. We hypothesize that this variability stems from additional rare variants in other genes, in addition to NF1 variants. The analysis of 32 NF1 patients revealed that those with solid cancers carried a higher average of cancer driver variants especially in DNA repair genes compared to those without (p < 0.05). An extended validation study using 217 NF1 carriers (71 cancer and 146 controls) from UK biobank confirmed significant enrichment of pathogenic (P), likely pathogenic (LP) and uncertain significant (VUS) variants in DNA repair genes, in NF1 patients with tumors (FDR ≤ 0.05). Furthermore, P/LP variants in other genes are shown in those patients with NF1 ancillary traits such as cognitive impairments, macrocephaly, and connective defects. This study provides novel evidence suggesting that additional genetic variants in other genes may contribute to the phenotypic variability observed in NF1, indicating that rare secondary mutational events could influence specific manifestations, adding complexity to its variable expressivity.