Rare variants modulating phenotype in NF1 carriers

Area of Science:

• Genetics
• Oncology
• Rare Diseases

Background:

• Neurofibromatosis type 1 (NF1) is a rare genetic disorder characterized by significant phenotypic variability.
• Manifestations range from benign growths and psychosocial issues to aggressive cancers and congenital anomalies.

Purpose of the Study:

• To investigate the hypothesis that additional rare genetic variants contribute to NF1's phenotypic variability.
• To identify specific genetic variants associated with cancer and other NF1-related traits.

Main Methods:

• Analysis of genetic variants in 32 NF1 patients, with a focus on cancer driver variants.
• Validation study using UK Biobank data from 217 NF1 carriers (71 with cancer, 146 controls).
• Assessment of pathogenic (P), likely pathogenic (LP), and uncertain significance (VUS) variants in DNA repair and other genes.

Main Results:

• NF1 patients with solid cancers showed a higher average of cancer driver variants, particularly in DNA repair genes (p < 0.05).
• A significant enrichment of P/LP/VUS variants in DNA repair genes was confirmed in NF1 patients with tumors (FDR ≤ 0.05).
• P/LP variants in other genes were associated with NF1 ancillary traits like cognitive impairments, macrocephaly, and connective tissue defects.

Conclusions:

• Additional genetic variants, beyond NF1 mutations, likely contribute to the wide spectrum of NF1 phenotypes.
• Rare secondary genetic events may influence specific NF1 manifestations, increasing disease complexity and variability.
• This finding offers new insights into the genetic underpinnings of NF1 expressivity.