Research: Genetic diseases, if father’s age increases, more risks for unborn child

The ‘new mutations’ that cause numerous genetic diseases are transmitted mainly through the father. The risk increases with age because the cells that give rise to spermatozoa (spermatogonia) and that contain these mutations replicate throughout life, thus progressively increasing in number. Furthermore, cells carrying the mutated gene may present a ‘clonal advantage’, that is, they replicate more than healthy cells, thus increasing the risk of transmitting a rare disease to one’s children. A new molecular mechanism underlying this process has been identified by a joint study by the Bambino Gesù children’s hospital in Rome and the University of Oxford published in the scientific journal The American Journal of Human Genetics.

The research focused on Myhre syndrome, a rare genetic disease caused by mutations in the Smad4 gene that arise de novo in spermatogonia. These mutations occur spontaneously during the division of germ stem cells during the DNA replication process. Researchers from the Molecular Genetics and Functional Genomics area of ​​the hospital have shown that the mutations that cause this disease always have a paternal origin. Researchers from the Mrc Weatherall Institute of Molecular Medicine at the University of Oxford have then highlighted how these mutations confer a proliferative advantage to germ stem cells, determining their clonal expansion.

This increased cell division is a process in some ways similar to that observed in cancer cells and increases the probability that a sperm carries a mutation that causes the disease. This risk increases with increasing paternal age. Finally, thanks to functional characterization studies, researchers at the Bambino Gesù hospital have identified the molecular mechanism that probably gives germline stem cells carrying the mutated Smad4 gene the proliferative advantage. These mutations would in fact cause the hyperactivation of an intracellular signaling pathway, known as the Mapk cascade, which is generally activated in response to the stimulation of growth factors as frequently happens in many oncological diseases.

Tartaglia, ‘study useful for improving genetic counseling but also relevant in terms of new knowledge’

The international multicenter study was conducted by analyzing samples from 18 patients diagnosed with Myhre syndrome and their parents and those of anonymous donors aged between 24 and 75 years. The demographic data of 35 families of American patients with Myhre syndrome were also analyzed.

“These results are relevant not only for their important implications in the field of genetic counseling and reproductive risk calculation, but also in terms of new knowledge,” explains Marco Tartaglia, head of the Molecular Genetics and Functional Genomics Unit at the pediatric hospital. “The study demonstrates the presence of clonal expansion in association with mutations that affect a protein that operates outside the signaling pathway previously associated with this phenomenon. This discovery suggests that, as paternal age increases, more molecular mechanisms may contribute to increasing the probability of transmission of a mutated gene that potentially causes disease to the unborn child.”