How the father’s older age influences the baby’s congenital disorders

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Sperm from older men can transmit mutations that cause congenital disorders to the baby, but there are mutations independent of paternal age that could occur in the testes before sexual maturation.

Pregnancy in older women is associated with risks for mother and child, such as the baby having congenital malformations, and it is also known that older men are more likely to father offspring with bone and heart malformations, such as achondroplasia – the form most common short-limb dwarfism–, Noonan syndrome, or neurodevelopmental disorders, schizophrenia and autism.

Now, a new study has shown that the relationship between paternal age and rare congenital disorders is more intricate than scientists had previously considered and that, although later parenthood increases the risk of passing on a new mutation that could cause a disorder congenital in children, certain mutations that can generate these disorders are also found in young men.

The findings have been published in Genome Biology and Evolution and indicate that, while the link between some pathogenic mutations increases with paternal age, others do not, and may even occur in the male testes before sexual maturity. This means that sperm from older fathers are more likely to transmit new mutations that would cause congenital disorders to their offspring, but that there are other mutations that are independent of paternal age.

“As a consequence, the incidence of mutations with possible consequences for the health of the offspring could be much more common in the population and, in some cases, independent of the age of conception,” the authors of the study explained in their article, which They have been led by researchers from the Johannes Kepler University (Austria).

Mutations in the male germline that affect offspring

The team of scientists collected sperm samples from anonymous donors aged 23 to 59 years and investigated the frequency of genetic mutation variants for 10 different variants of the fibroblast growth factor receptor 3 (FGFR3) protein, which is found in tissues such as cartilage, brain, intestines and kidneys in humans.

The researchers found two FGFR3 variants associated with two rare diseases related to older paternal age. One of these variants is associated with achondroplasia, and the other variant is associated with thanatophoric dysplasia – a serious and usually fatal skeletal disorder in children characterized by a disproportionately small rib cage and extremely short limbs – and also increased with age. paternal

The research team noted that many other FGFR3 variants were not related to paternal age. Notably, the variant associated with CATSHL syndrome (camptodactyly-tall stature-scoliosis-hearing loss) was not more common in the sperm of older men compared to that of younger men. “Young parents also face a higher risk of having children with pathogenic mutations,” said Irene Tiemann-Boege of the Institute of Biophysics at Johannes Kepler University and lead author of the study.

“Sperm can accumulate errors in DNA replication that result in genetic problems, so the older the male, the greater the genetic risk for the offspring.”

“The concept of advanced age in men is elusive, because unlike women, where age has an obvious influence on reproductive capacity, and from a certain value it significantly affects it, these changes associated with age of men occur in a more gradual way, without obvious jumps, which makes it difficult to define a threshold value,” said Nicolás Garrido Puchalt, director of the IVI Foundation (Valencian Institute of Infertility) and director of research administration at IVIRMA. Global Research Alliance in Valencia in statements to SMC Spain.

“One of the reasons why there is this risk associated with the male’s age is due to an accumulation of mutations in the germ line that gives rise to sperm, since they are cells with a high rate of division throughout the male’s life, which “They can accumulate failures in DNA replication that result in genetic problems, so that the older the male is, the more of these he would accumulate and, therefore, the greater the genetic risk for the offspring.”

“Together, these results provide new knowledge on the mutagenesis of driver mutations and the resulting mosaicism in the male germ line, with important consequences for the transmission and recurrence of associated disorders, allowing us to reaffirm previous concepts regarding the influence the age of the man at the time of conception and the risk for the offspring,” concludes the expert.

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