Will my child inherit my fertility problems?

Infertility is defined as the inability to conceive after 12 months of regular unprotected intercourse. It is estimated that in 35% of cases it is caused by female factors, in 20% by male factors, in 40% by mixed factors and in the remaining cases it is of unknown origin.

Is infertility hereditary?

The origin of infertility is diverse, and it’s estimated that in 20% of people it has a genetic origin, while in the remaining 80% it is caused by non-hereditary conditions, such as acquired diseases, age, lifestyle habits, environmental factors, etc.

When infertility is of genetic origin, depending on the cause, it may or may not be inherited by the sons and/or daughters of the infertile couple. The possibilities of transmission to offspring of genetic conditions that cause infertility are detailed below.

What genetic factors may decrease the chance of parenthood?

Transmission by both partners

Structural chromosomal alterations

Structural chromosomal alterations may be due to the exchange of segments between chromosomes (reciprocal translocations) or the fusion of two acrocentric chromosomes (Robertsonian translocations).

These translocations don’t directly affect the individuals who have them, as there’s no gain or loss of genetic material. However, it does pose a fertility problem, as this chromosomal rearrangement leads to the production of eggs and sperm with an unbalanced genetic load. These gametes will give rise to unbalanced embryos, leading to repeated miscarriage, implantation failure or newborns with congenital anomalies.

Numerical chromosomal abnormalities

Numerical chromosomal abnormalities are the gain or loss of a chromosome. The most common numerical alterations in reproductive age are those that affect the sex chromosomes and give rise to genetic syndromes, the most common being Klinefelter Syndrome (47,XXY), Turner Syndrome (45,X0), Double Y Syndrome (47,XYYY) and Triple X Syndrome (47,XXX).

In addition, these disorders can be found in mosaic, i.e. it is possible for an individual to have two or more populations of cells that differ in their genetic make-up.

In these cases, patients would also produce unbalanced gametes, leading to the same fertility problems as explained in the previous section.

Female transmission

Fragile X syndrome (premutation)

Fragile X syndrome is the most common form of inherited intellectual disability and is caused by mutation of the FMR1 gene. It is estimated that 1/230 females and 1/800 males are carriers and 1/4000 males and 1/6000 females are affected.

In addition, the gene’s premutated form also has an effect on female carriers. It’s estimated that 20% of these patients have low ovarian reserve or early menopause, compared to 1% of the normal population. Therefore, daughters of these patients who inherit the premutated allele will also be more likely to have ovarian failure.

In addition, the impact on offspring may be compounded, as the premutation tends to increase in size as it passes from one generation to the next. If the 200 repeats are exceeded, a son will have Fragile X syndrome and a daughter will be a carrier.

Genes involved in ovogenesis

Recent studies have shown that mutations in genes involved in ovogenesis (both in the development of the ovarian follicle and in cell division and DNA repair) can lead to early ovarian failure. This pathology affects 1% of women under the age of 40 whose ovaries have totally or partially ceased to function.

These mutations, mostly of dominant inheritance, can be passed on to offspring and cause the same fertility problem in daughters. However, if they are detected in time using genetic tests such as IBGenFOP, it’s possible to plan childbearing, both by bringing forward the pregnancy and by vitrifying oocytes.Genes implicados en la ovogénesis

Endometriosis and ovarian cancer.

Some diseases that may lead to fertility problems, such as endometriosis and ovarian cancer, also have a hereditary component. In the case of endometriosis, it’s difficult to determine the percentage of cases that have a genetic origin, although it is known that there is a hereditary component. On the other hand, for ovarian cancer, it’s estimated that at least 20% of cases are of hereditary origin and are mainly associated with the BRCA1, BRCA2, MMR, RAD51 and BRIP1 genes. 

Human transmission

Microdeletions of the Y chromosome

The Y chromosome encodes the genetic information necessary for differentiating males from females and for the formation of spermatozoa. For this reason, the loss of small fragments of this chromosome leads to changes in the sperm count. Depending on the fragment deleted, these alterations are of varying severity and may produce few spermatozoa (oligozoospermia) or none at all (azoospermia).

It is estimated that 10% of males with alterations in the seminogram may be missing certain regions of the Y chromosome. Identifying whether a male has these alterations not only helps to establish the cause of the problem, but also to offer appropriate genetic counselling to discern whether the fertility problem will be inherited by his sons.

Genes involved in spermatogenesis

Mutations that occur in genes involved in spermatogenesis can also cause infertility. These mutations can produce a deleterious effect on the gene, resulting in a loss of function of the gene, as some stage of the sperm formation process cannot be carried out.

In order to diagnose these cases, we have developed the IBGen SPERM test, in which 426 genes are studied by massive sequencing. It is indicated in cases of azoospermia, severe oligozoospermia, asthenozoospermia and oligoteratozoospermia. In case of detecting a mutation with a deleterious effect, as it is mostly dominant inheritance, there would be a 50% chance that the male offspring would have the same fertility problem.

Should I undergo genetic testing before an Assisted Reproduction treatment?

Thanks to advances in molecular biology and genetics and the incorporation of specialised laboratories in these areas in assisted reproduction centres, it’s becoming increasingly more accessible for patients to undergo genetic tests that can reveal the origin of the couple’s fertility problem if it is genetic in origin.

In most couples with a history of infertility, implantation failure or repeated miscarriages, karyotyping is indicated to rule out chromosomal alterations in both partners.

In addition to karyotyping, in men with spermiogram alterations, the study of cystic fibrosis (CFTR gene) and the study of microdeletions of the Y chromosome may be indicated, while in women with low reserve, the study of fragile X syndrome (FMR1 gene) is also recommended.

Mónica Hortal, biotechnologist at Instituto Bernabeu Biotech