Learn about what reproductive health has to do with family history and genes, and which genetic conditions might make conceiving difficult. We explain how genetic testing works and when it may be a good idea.

Does infertility run in families? If your parents had a hard time getting pregnant, does it mean that you will too? Could a genetic abnormality be preventing you from getting pregnant? This article explores what reproductive health has to do with family history and genes, and which genetic conditions might make conceiving difficult. It further dives into how genetic testing works and when it may be a good idea.

What is Infertility?

Infertility is commonly defined as the inability of a couple to conceive after 12 or more months of regular unprotected intercourse. It is a common problem, affecting 1 in 6 individuals worldwide.

Infertility can be the result of a multitude of genetic and nongenetic factors; its causes range from hormonal problems to lifestyle factors to parental age and environmental influences. However, many of the common disorders underlying female and male infertility have a genetic component. While some of these genetic abnormalities are passed down through families, others can occur randomly.

Read on to learn about the common genetic causes of male and female infertility, and how genetic factors are tested for, both before and after conception.

Why is understanding genetic causes of infertility important?

Genetic factors are significant in both male and female cases of infertility.

It is believed that genetic abnormalities are a factor in many infertility cases. Therefore, especially when there are indications that a genetic disorder may be present, there may be reason to undertake genetic testing to examine the genome. This is the set of genetic information contained within an individual’s chromosomes. Genetic causes of infertility may also play a role in cases where it is unclear why a couple is unable to conceive or is experiencing repeated miscarriage. These cases, called idiopathic infertility, arise when a cause cannot be found despite various fertility analyses, such as blood tests, semen analysis and imaging tests.

The process of genetic testing can also help to identify genetic diseases that can be passed down to one’s offspring. In cases where individuals have a family history of a disorder, this may be recommended.

Furthermore, the use of assisted reproductive technology (ART) such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), can enable couples who otherwise wouldn’t have been able to get pregnant. However, ARTs, and especially ICSI, can be associated with an increased risk of abnormalities, for e.g. cardiovascular, gastrointestinal or chromosomal birth defects, in babies conceived via these methods. Thus, understanding the genetic basis of fertility problems can be helpful in providing guidance and fertility treatment to couples struggling with infertility.

The main genetic causes of female and male infertility are different; below, we discuss them separately in turn.

Genetic causes of female infertility

Chromosomal abnormalities

  • Trisomy X (an incorrect chromosome number or aneuploidy) involves three copies of the X chromosome instead of the usual two in women. It occurs in 1 in 1,000 female births, and is a cause of primary ovarian insufficiency, which causes women to stop ovulating before the age of 40. However, it is also possible for women with trisomy X to have undisturbed fertility.
  • Turner syndrome, also known as monosomy X, occurs in 1 in 2,500 female births. It refers to females with only one X chromosome. It associated with characteristic features such as skeletal abnormalities, heart defects, short stature and a webbed neck. It also causes complications in the reproductive system, including absent periods (amenorrhea) or ovarian failure.
  • Copy number variants. Newer studies have shown that changes in DNA, such as when small  amounts are added (microinsertions), missing (microdeletions) and repeated (microduplications) are associated with female infertility.

Single-gene disorders

As their name implies, these disorders are ones in which a change of DNA (mutation) in one or more genes is associated with infertility. In women, these disorders include:

  • Fragile X syndrome. Characterised by physical features such as a long face and large ears, as well as intellectual disability, Fragile X syndrome and its associated mutations in the FMR1 gene are associated with primary ovarian insufficiency.
  • Galactosemia. This is a metabolic disorder in which individuals are intolerant to dietary galactose and generally have to follow a restricted diet. Primary ovarian insufficiency and hypergonadotropic hypogonadism (a condition involving reduced function of the ovaries in response to too much gonadotropin produced by the pituitary gland) are commonly seen in women with this disorder. In some studies of this disorder, the GALT gene has been implicated.
  • Sickle cell disease (SCD). Involving mutations to the HBB gene, SCD causes more severe problems for male fertility. However, challenges in conceiving are also documented for women with SCD.
  • Primary ovarian insufficiency (POI). In POI, women stop ovulating before 40 years of age. In addition to being linked with the FMR1 gene, several other genes are found to be linked to the disorder.
  • Early or premature menopause. This is when menopause occurs as early as age 40. As with POI, it is found to have a genetic underpinning.
  • Fibroids (known medically as leiomyomas) can pose challenges to conception and pregnancy, and are associated with mutations in genes such as MED12.

Polygenic and complex genetic causes

  • Endometriosis. This condition involves endometrial tissue growing outside of the womb, causing pain and potentially affecting the functioning of the ovaries and fallopian tubes. While some candidate genes have been identified, the effort to pinpoint the specific genetic causes of this disease is ongoing. What is known is that when a woman has endometriosis, the risk of her first-degree female relatives having it also is ten times higher.
  • Polycystic ovary syndrome (PCOS). This is an endocrine disorder characterised by menstrual irregularities, multiple cysts on the ovaries, and hirsutism (excess body hair). It is also associated with metabolic problems, such as obesity and type 2 diabetes. PCOS is found to run in families. As no specific genes have yet been determined, however, the disorder remains idiopathic in nature.

Genetic causes of male infertility

The genetic causes of infertility for men fall into two main categories, as outlined below.

Chromosomal abnormalities

Chromosomal abnormalities account for approximately 5% of cases of male infertility, and 15% of cases of men with azoospermia. They include:

  • Klinefelter syndrome, a type of aneuploidy involving an extra X chromosome, so that a male’s sex chromosomes are XXY instead of XY. This often manifests in low testosterone production and limited or no production of sperm.
  • Kallmann syndrome. This disorder involves delayed or absent puberty and is also associated with anosmia, or the inability to smell. It can occur and hinder fertility in both sexes, but it is more common among males.
  • Chromosomal rearrangements, such as translocations and inversions, are pieces of chromosomes that are moved around, switched or missing. They can impair male fertility.
  • Y chromosome microdeletions. As the name suggests, in this case some small parts (e.g. single genes) of the Y chromosome are missing. Particularly microdeletions in the azoospermia factor (AZF) region of the Y chromosome, which influences sperm production, can negatively impact male fertility by interfering with spermatogenesis.
  • As with women, copy number variants, in which individuals have varying numbers of copies of specific DNA segments, are a factor in male infertility.

Single-gene disorders

A number of genes are implicated in male fertility disorders. Some of these include:

  • Cystic fibrosis transmembrane conductance regulator (CFTR): mutations in this gene can lead to congenital bilateral absence of the vas deferens (CBAVD). The vas deferens transports sperm from the testicles to the penis; its absence from birth in this condition is a cause of obstructive azoospermia and male factor infertility. In addition, if both parents have the CTFR gene mutation (are carriers) and both pass it on, then their child will have cystic fibrosis, which is also a cause of male infertility.
  • Androgen receptor (AR): mutations in this gene can lead to androgen insensitivity (inability of the male body to respond to androgens like testosterone) and infertility in males.
  • Aurora kinase C: mutations in the AURKC gene are associated with problems in sperm morphology (the form of sperm).
  • Sickle cell anemia (SCD). In men with sickle cell anemia, there is a high prevalence of sperm abnormalities, including low sperm count, and subpar motility (movement) and morphology. One study found that 91% of male patients with the disorder had at least one abnormal sperm parameter before treatment.

Genetic Testing: An Overview

Genetic evaluation, in the fertility context, refers both to genetic testing and genetic counseling (receiving advice and guidance based on test results).

One of the main tools used to assess suspected or potential genetic problems is chromosome analysis (also known as karyotyping). This detects chromosomes that are damaged, missing, or too many in number. It involves processing a blood sample in a laboratory.

Karyotyping may be recommended for individuals prior to beginning fertility treatment in the following scenarios:

A kind of genetic screening called preconception carrier screening may also be recommended to see if one or both members of a couple are carriers of certain genetic disorders that can be passed down. This may be based on reproductive age of the couple, family history, personal medical history, or membership in ethnic groups in which certain disorders are more common.

What happens when a genetic disorder is diagnosed?

The next step for a couple who receives a diagnosis of a genetic disorder may be to seek fertility-restoring treatment, when it is available. In other cases, the focus may be on reducing the likelihood of passing the disorder on to their offspring. Options for this include:

  • IVF instead of ICSI. In conception without intervention, usually the healthiest sperm are those that end up fertilising egg cells. When undertaking assisted reproduction in the context of genetic disorders, IVF (involving multiple sperm competing for an egg within a petri dish) can be a better option than ICSI (in which a single sperm is injected directly into the egg). This increases the chances that a healthy sperm will be the one to fertilise the egg.
  • Preimplantation genetic diagnosis. This involves adding a step to IVF treatment, in which one or more embryos are tested (via removal of one of their cells) for gene mutations before being transferred to a woman’s uterus.
  • Noninvasive prenatal diagnosis (NIPD), which is able to sample fetal DNA via a sample of the mother’s blood as early as about 10 weeks of gestation.
  • Amniocentesis and chorionic villis sampling. These tests, performed usually in the second trimester of pregnancy, involve sampling amniotic fluid or placental tissue in order to examine the chromosomes of a fetus.
  • Use of a sperm or egg donor. In Switzerland, however, egg donation is prohibited.

Takeaway

Disorders at the level of entire chromosomes or genes within them contribute to male and female infertility. Genetic testing or screening may be done in order to determine cause(s) of infertility, to identify genetic disorders that may be passed on to a couple’s offspring, or to reduce the likelihood of abnormalities resulting from assisted reproductive technologies. These tests and procedures can be undertaken either at the preconception, preimplantation, or prenatal stage.

Do you have questions about genetic aspects of fertility, or want advice? Contact our caring team of fertility specialists who can help guide you through this topic. Reserve your spot for a free consultation today.