The Risk of Transmission of Genetic Prion Diseases is Greater Than 50

Inherited prion diseases follow autosomal dominant inheritance with a theoretical 50% transmission risk per pregnancy. Transmission ratio distortion (TRD)-deviation from expected Mendelian ratios-has been documented in other genetic disorders but never systematically studied in prionopathies. We aimed to determine whether TRD occurs in families with inherited prion diseases-specifically familial Creutzfeldt-Jakob disease due to the p.E200K variant and fatal familial insomnia caused by the p.D178N variant-and to assess whether transmission patterns differ by parent sex.

We analyzed 24 pedigrees (12 per variant) comprising 65 nuclear families with 151 offspring. Transmission ratios were calculated and compared to expected 50% Mendelian inheritance using generalized estimating equations. Sex-specific transmission patterns were evaluated for both maternal and paternal carriers.

Overall transmission rates were 67.1% for p.D178N (95% CI: 56.3%-77.9%, p < 0.05) and 70.5% for p.E200K (95% CI: 60.4%-80.6%, p < 0.001), representing deviations from expected Mendelian ratios. Sex-specific analysis revealed maternal transmission of 67.5% for p.D178N (p < 0.05) and 67.3% for p.E200K (p < 0.05). Paternal transmission showed 66.7% for p.D178N (p = 0.056) and 78.3% for p.E200K (p < 0.05), with the latter showing pronounced paternal bias.

This study provides the first systematic evidence of TRD in inherited prion diseases, with both variants showing clinically meaningful deviations from Mendelian inheritance. These findings challenge current genetic counseling assumptions of 50% inheritance risk and suggest that actual transmission probabilities are 17%-21% higher than traditionally estimated. Risk assessment protocols for prion diseases require updating to incorporate variant-specific and sex-specific transmission patterns, particularly the strong paternal bias observed with p.E200K.