Author: Guiomar Pérez de Nanclares
In hereditary prion diseases, the actual probability of transmitting the pathogenic mutation from a carrier parent to their offspring is significantly higher—between 17% and 21% higher—than expected according to classical Mendelian inheritance of 50%, with a marked bias in paternal transmission for certain genetic variants.
Prion diseases are serious and almost always fatal neurodegenerative disorders caused by the alteration of the prion protein, encoded in the PRNP gene. Hereditary forms (such as familial Creutzfeldt-Jakob disease, fatal familial insomnia, or Gerstmann-Sträussler-Scheinker syndrome) account for 10-15% of cases and are transmitted from one generation to the next following an autosomal dominant pattern (i.e., it is sufficient for one person to have one of the two copies of the PRNP gene, either paternal or maternal, with an alteration to cause the disease). Furthermore, this means that, according to Mendel's classical laws of genetics, each descendant has a 50% chance of inheriting the mutation from a carrier parent.
The study published by Dr Kortazar and colleagues analysed 24 family pedigrees with hereditary prion diseases, specifically 12 with the genetic variant p.D178N (fatal familial insomnia) and 12 with the variant p.E200K (familial Creutzfeldt-Jakob disease), totalling 65 nuclear families and 151 individuals with known genetic status (either through direct genotyping or by establishing their genetic status based on their family history). We define a nuclear family as one composed of a carrier parent and at least one descendant. The researchers analysed how often a carrier parent transmitted the alteration to their descendants and how often they did not, and compared this with the expected 50%.
The results indicated that the actual probability of inheriting the mutation is significantly higher than the expected Mendelian 50%. Specifically, the observed transmission was 67.1% for the p.D178N variant and 70.5% for the p.E200K variant, representing a 17% to 21% increase in the risk of inheriting the alteration. In addition, there were differences depending on the sex of the carrier parent: in the p.E200K variant, transmission by the father was 78%, significantly higher than the 67% observed in mothers. In the p.D178N variant, transmission was similar in mothers and fathers, both around 67%.
Why does this deviation from the expected 50% occur?
This phenomenon is known as transmission ratio distortion (TRD), a non-Mendelian mode of inheritance that occurs when one allele (one of the two copies of each gene) is transmitted more frequently to offspring due to biological mechanisms. Advantages during gamete formation (eggs and sperm), early embryonic survival, or specific functions of the prion protein in reproduction may be involved. For example, in the case of the p.E200K variant, elevated paternal transmission could be related to the expression of the prion protein in sperm, which could influence the competition or viability of sperm carrying the mutation.
What do these results mean for families and genetic counselling?
These results force us to reconsider the risks communicated in clinical genetics. The actual risk of inheriting hereditary prion diseases is higher than previously assumed, especially in certain cases and variants. Therefore, genetic counselling must be updated to reflect these risks greater than 50%, which may affect reproductive decisions and early diagnosis strategies.
Access the original article here (in English).
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