Transmission ratio distortion of NF1 variant alleles in familial neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a common autosomal dominant tumor-predisposition syndrome (approximately 1:3000 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.

We analyzed transmission patterns in 322 NF1 families across 4 well-characterized cohorts, applying strict inclusion criteria to minimize ascertainment bias and to exclude possible mosaic cases. Subsampling and large-scale random downsampling analyses were used to assess whether cohort size or other confounders could account for the observed transmission pattern.

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 clonal selection of NF1-null cells within the early embryonic germline, a mechanism grounded in established NF1 tumor biology but not previously implicated in patterns of inheritance.

Our findings identify a previously unrecognized feature of NF1 genetics and suggest germline selection as a potential driver of transmission ratio distortion, with implications for clinical practice, prenatal diagnostics, and reproductive counseling.