Gene variants linked with congenital disorders observed in young fathers too

Both young and old fathers carry gene variants associated with congenital disorders in children, which have so far been linked with delayed fatherhood, new research has found.

While it is recognised that delayed fatherhood is linked with the child inheriting a new mutation that might result in a higher risk of a congenital disorder, researchers have found that the link is more complex with some variants observed in both young and old men.

The researchers, led by those from Johannes Kepler University, Austria, collected sperm samples from anonymous male donors aged 23 to 59 at clinics in the country.

They investigated the variant frequency for genetic mutations for ten different variants of the fibroblast growth factor receptor 3 (FGFR3) protein, which is expressed in humans in tissues including cartilage, and the brain, intestines, and kidneys.

The investigators found that the FGFR3 variant associated with Achondroplasia, the most common form of short-limbed dwarfism, does increase with the father’s age.

Another variant that was found to observed to increase with paternal age was the one associated with Thanatophoric dysplasia – a severe and usually fatal skeletal disorder in children characterised by a disproportionately small ribcage and extremely short limbs.

However, the researchers also found many other FGFR3 variants that were not connected to the father’s age, such as the one associated with CATSHL (Camptodactyly-tall stature-scoliosis-hearing loss) syndrome, a rare genetic disorder consisting of camptodactyly, tall stature, scoliosis and hearing loss. While the medical condition camptodactyly involves permanent bending of one or more fingers or toes, scoliosis is one where a person’s spine has an abnormal curve.

The team found that the CATSHL syndrome variant was not more common in sperm of older men compared to younger men.

“Young dads also face a higher risk of having kids with pathogenic mutations,” said Irene Tiemann-Boege, Institute of Biophysics, Johannes Kepler University, and lead author of the study published in the journal Genome Biology and Evolution.

Genetic mutations that can result in congenital disorders – called driver or selfish mutations – are more common in the male germline, or cells carrying genetic material from generation to generation, for example sperm and egg cells. Further, these mutations are thought to be more common in the sperm of older men, the researchers said.

However, despite the importance of driver mutations in the male germline due to their high incidence and increased frequency, as well as their potential pathogenic effects, it is not yet understood where the mutations really come from and why they are found so often, the team said.

Their investigation indicates that while the link between some pathogenic mutations increases with paternal age, others do not and may even occur in the father’s testis before sexual maturity, they said.

“As a consequence, the incidence of mutations with potential health consequences in the offspring might be much more common in the population and in some cases independent of the age of conception,” the researchers wrote.