Transmission ratio distortion of NF1 mutant alleles in familial Neurofibromatosis type 1.

PURPOSE: Neurofibromatosis type 1 (NF1) is a common autosomal dominant tumor-predisposition syndromes (∼1:3,000 worldwide), involving pigmentary, skeletal, and neurodevelopmental features, and lifelong tumor risk. Although NF1 has been traditionally assumed to follow Mendelian transmission, our analyses reveal a consistent deviation from this expectation. METHODS: We analyzed transmission patterns in 322 NF1 families across four well-characterized cohorts, applying strict inclusion criteria to minimize ascertainment bias and exclude possible mosaic cases. Sub-sampling and large-scale random down-sampling analyses were used to assess whether cohort size or other confounders could account for the observed transmission pattern. RESULTS: Among 701 offspring, 61.1% were diagnosed with NF1, significantly exceeding the 50% expected under Mendelian inheritance (p = 5 × 10-9). This robust transmission ratio distortion was present in both female (62.8%) and male (58.5%) transmitters. We propose that this pattern is most consistent with a mechanism involving clonal selection of NF1-null cells within the early embryonic germline, a concept conceptually grounded in established NF1 tumor biology but not previously linked to inheritance pattern. CONCLUSION: Our findings uncover a previously unrecognized feature of NF1 genetics and suggest germline selection as a driver of transmission distortion, with implications for clinical practice, prenatal diagnostics and reproductive counseling.