Unfulfilled desire to have children

For many couples, the desire to start a family is a central life goal. However, around 15–20% of all couples in Austria struggle with an unfulfilled desire to have children. The reasons are varied and affect both women and men. A thorough diagnostic work-up of the causes is crucial in order to identify the best possible treatment options.

The importance of genetic diagnostics

When couples have difficulty conceiving, genetic factors can play an important role. Genetic diagnostics help identify the exact causes of the fertility disorder, which can be crucial for choosing the right treatment.

Genetic causes

Genetic causes in men

A common cause of male infertility is impaired sperm production, which may be due to genetic issues. For example:

Disorders of spermatogenesis

These refer to problems in the process of sperm formation in the testes, which can be disrupted by genetic or other factors. Such disorders can lead to reduced sperm count and quality, significantly impairing fertility. For example, oligozoospermia results in a lower sperm concentration in the ejaculate, while azoospermia means no sperm are present at all. Treatment options vary depending on the cause; in some cases, testicular sperm extraction (TESE) followed by in vitro fertilisation (IVF) may be considered.

Chromosomal abnormalities

Such as Klinefelter syndrome (47,XXY) can negatively affect sperm production. These abnormalities affect the number or structure of chromosomes and are detectable in around 15% of men with azoospermia. After diagnosis, genetic counselling is essential to understand the impact on fertility and to discuss appropriate treatment options.

Y-chromosome microdeletions

These are small genetic losses in specific regions of the Y chromosome that are necessary for spermatogenesis. These microdeletions, particularly in the AZF regions (azoospermia factors), are common genetic causes of non-obstructive azoospermia. Such deletions are found in around 15–20% of men with this form of azoospermia and in around 7–10% of men with severe oligozoospermia. A precise diagnosis is important because, with certain deletions such as in the AZFc region, it may be possible to retrieve sperm via TESE.

CFTR gene mutations

Known as the main cause of cystic fibrosis, they can also lead to obstructive azoospermia, in which the vas deferens are blocked or not properly developed. This genetic change affects around 80% of men with congenital bilateral absence of the vas deferens (CBAVD), a specific form of azoospermia. Detailed genetic analysis is essential for diagnosis and treatment, as it helps determine the best possible reproductive options, including techniques such as TESE or intracytoplasmic sperm injection (ICSI).

Genetic causes in women

Genetic factors can also play a role in infertility in women.

Hypergonadotropic hypogonadism

This is a form of ovarian insufficiency in which genetic causes such as Turner syndrome (45,X) may play a role. These chromosomal abnormalities impair normal ovarian function and can lead to infertility. Around 10% of affected women have such a sex-chromosome aberration. In these cases, chromosomal analysis is important to clarify the cause of infertility.

Premutations in the FMR1 gene

These are another genetic cause of infertility in women. These premutations increase the risk of premature ovarian insufficiency, in which the ovaries stop functioning early. Women with such genetic changes also have an increased risk of having children with fragile X syndrome, a condition associated with intellectual disability and behavioural disorders.

Hypogonadotropic hypogonadism

This occurs in women when the production of gonadotropic hormones, which are essential for ovarian function, is disrupted. This rare condition is often genetic and can be caused by mutations in various genes. The condition is relatively uncommon but affects a woman’s ability to conceive naturally.

Hyperandrogenaemia

This describes an increased level of male hormones in the blood and is often caused by genetic disorders such as congenital adrenal hyperplasia (CAH). This disorder can impair fertility and requires specialised genetic diagnostics to identify the underlying enzyme defect and enable appropriate treatment.

Genetic causes in couples

KIR and HLA-C genotypes

The interaction between natural killer cells (NK cells) in the uterine lining and the developing embryo is among the immunological factors that significantly influence the establishment and continuation of a pregnancy. This interaction is mediated by killer cell immunoglobulin-like receptors (KIR), which are expressed by uterine NK cells, and HLA-C antigens on the surface of the trophoblast. Both the KIR gene family and the HLA-C molecules exhibit extremely high genetic variability. Although the complex interplay between these two gene systems has not yet been fully clarified, there is evidence that certain combinations of maternal KIR genotypes and fetal HLA-C molecules are associated with a higher risk of implantation failure, recurrent miscarriage, and pregnancy complications such as preeclampsia.

KIR and HLA-C genotyping as part of reproductive medicine treatment is performed by analysing the genomic DNA of the couple trying to conceive. This involves assessing which sets of activating and inhibitory KIR are present in the woman and determining the man’s HLA-C genotype (HLA-C1/C1, HLA-C1/C2 or HLA-C2/C2). If gamete donation is required for treatment, the egg donor or sperm donor will also undergo HLA-C genotyping.

At present, immunological understanding of the KIR–HLA-C interaction is not sufficient to conclusively establish a causal relationship between specific parental genotypes and the occurrence of implantation failure, recurrent miscarriages, or pregnancy complications. However, various studies show that the information obtained from KIR and HLA genotyping can help

determine the optimal number of embryos for transfer in an IVF cycle

prevent possible complications during pregnancy, and

in the case of gamete donation, select a donor whose HLA-C genotype is immunologically compatible with the future mother’s KIR genotype

Relevance for affected couples

For couples with an unfulfilled desire to have children, it is important to undergo comprehensive evaluation to identify the exact cause of the fertility disorder. Genetic diagnostics play a key role here, as they help develop targeted treatment strategies. In many cases, an assisted reproduction technique such as in vitro fertilisation (IVF), combined with genetic counselling and diagnostics, can lead to the desired success.

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