Over-transmission of NF1 mutant alleles in Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant tumor-predisposition syndromes ([~]1:3,000 worldwide), caused by pathogenic variants in the NF1 gene. NF1 is clinically diverse, involving pigmentary, skeletal, and neurodevelopmental features, alongside a lifelong risk of benign and malignant tumors. NF1 encodes neurofibromin, a negative regulator of RAS-MAPK signaling, and behaves as a classic tumor suppressor, with tumorigenesis requiring biallelic inactivation. Here, we analyzed transmission patterns in 322 NF1 families across four well-characterized cohorts, applying strict inclusion criteria to minimize ascertainment bias and avoid potential mosaic cases. Among 701 offspring, 61.1% were diagnosed with NF1, a significant excess over the 50% expected under Mendelian inheritance (p = 3 x 10-). This transmission ratio distortion (TRD) was observed in both female (62.8%) and male (58.5%) transmitters. To test whether cohort size or other confounders could explain this bias, we performed sub-sampling and large-scale random down-sampling analyses, which confirmed robust TRD independent of parental sex or sample size. We assessed plausible biological mechanisms for our findings and propose that the TRD observed in NF1 is most consistent with a novel mechanism involving clonal selection of NF1-null cells within the early embryonic germline, a concept rooted in established NF1 tumor biology. These findings uncover a novel aspect of NF1 biology with direct implications for clinical practice, prenatal diagnostics and reproductive counseling. Significance StatementNeurofibromatosis type 1 (NF1) is a common dominant cancer predisposition syndrome caused by mutations in the NF1 gene. Using data from more than 700 offspring in 322 families, we show that mutant alleles are transmitted more frequently than expected, violating Mendelian inheritance. This phenomenon, known as transmission ratio distortion (TRD), is best explained by germline selection mechanisms analogous to those driving clonal expansion in NF1 tumors. Our findings reveal a previously unrecognized aspect of NF1 genetics with direct implications for reproductive counseling. More broadly, they suggest that germline selection may be an underrecognized driver of human inheritance and disease risk.