Genetics in medicine : official journal of the American College of Medical Genetics · 2026
Transmission ratio distortion of NF1 variant alleles in familial neurofibromatosis type 1.
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Pei Yang, Browne Andrew, Creus-Bachiller Edgar, Lázaro Conxi, Castellanos Perez Elisabeth, Upadhyaya Meena, Riccardi Vincent M, Wallace Margaret R, Goriely Anne
Аннотация
PURPOSE: 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.
METHODS: 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.
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 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.
CONCLUSION: 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.
METHODS: 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.
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 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.
CONCLUSION: 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.