What causes genetic disorders

Genetic causes of infertility

Infertility is a heterogeneous disorder that affects around 10–15% of all couples. It can be based on a variety of disorders. The respective cause can affect both the man, the woman and both partners. On the following pages we would like to inform you about the most important genetically determined causes, their significance and the diagnostic options.

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According to a WHO definition, infertility is defined as the failure to conceive despite regular unprotected sexual intercourse over a period of at least twelve months. About 10–15% of all couples are affected. Information on the frequency of the causes varies. The cause of infertility is 30% in men or women, in around 30% in both partners, in around 10% of cases the assignment remains unclear. Fig. 1 shows the possible assignment.

Genetic causes (chromosome changes and monogenic disorders) are responsible for 10–20% of the male (Fig. 2) and for 5–10% of the female causes of fertility disorders.

Since the exact knowledge of the cause of the fertility disorder is of great importance for the specific treatment, a comprehensive clarification of the cause should always be sought. The clarification should include a family history (disabilities, abortions, infertility) and additional examinations.

(Physical) examination findings, possibly also from other affected family members, as well as the hormonal status are important. If a familial disorder is suspected, clarification should be sought with an affected person.

In the following explanations, the recommendations of AWMF S2k guideline diagnostics and therapy before assisted reproductive medicine treatment (Feb. 2019) and summarized here in their main recommendations (in highlighted boxes).

1. Genetic causes of male infertility

The most important indication of a genetic male cause of a fertility disorder is a pathological semen analysis. Depending on the result of an andrological basic diagnosis, a specific genetic examination should be arranged as part of a genetic counseling if there is a corresponding suspicion.

Important genetic causes of male infertility include chromosomal disorders, microdeletions of the AZF locus of the Y chromosome and mutations in individual genes such as the CFTR gene, which is responsible for cystic fibrosis.

Fig. 2: Genetic causes in men with infertility. (after Tüttelmann, 2018)

In an unselected collective of affected men, a genetic cause could be identified in 4.3%, whereas in men affected by azoospermia this rate was 20.6% (Fig. 2).


1.1. Non-obstructive spermatogenesis disorder

1.1.1. Chromosomal disorders

Chromosomal disorders have an incidence of 0.3–0.5% in the general population. Chromosomal aberrations were found in around 15% of the men with azoospermia examined, with men with hypergonadotropic azoospermia in around 20% and men with normogonadotropic azoospermia in around 5% having a chromosomal disorder (Donker et al., 2017). The most important disorder is Klinefelter syndrome (47, XXY).

Fig. 3 shows a frequency distribution of chromosomal disorders depending on the sperm finding as a result of the meta-analysis by Dul et al. (2010).

In the case of non-obstructive azoospermia or severe oligospermia (<5 million / ml), a chromosome analysis should be carried out after other causes have been excluded.

Fig. 3: Proportion of abnormal chromosome findings in men with different spermiogram findings (according to Dul. Et al. 2010)

1.1.2. AZF deletions of the Y chromosome

Microdeletions in the azoospermia factor (AZF) region of the Y chromosome are rare in the normal population (approx. 1: 4,000). They are found in less than 2% of infertile men. A distinction is made between three regions AZFa, AZFb and AZFc, which contain different genes that are important for spermatogenesis (Fig. 4).

Azoospermia is present in 100% of patients with AZFa and b deletions. In patients with AZFc deletions, the findings vary from azoospermia in 62% to oligospermia (5–10 million / ml) in approx. 2%.

The specific molecular genetic analysis and characterization of the deletion is of great importance for the question of assisted reproductive technology (ART). In about 50% of men with azoospermia and AZFc deletions, sperm can be detected in the testicular tissue.

Successful fertilizations have been reported in patients with AZFb deletion. This is not the case in patients with deletions in other regions (Sertoli cell only syndrome).

In the case of non-obstructive azoospermia or severe oligospermia (<5 million / ml), after excluding other causes, an analysis for AZF microdeletions (AZFa, b, c) should be carried out.

1.1.3. Monogenic spermatogenesis disorders

The cause of non-obstructive spermatogenesis disorders is unknown in up to 80%, depending on the study. A monogenic cause is only present in a small proportion of affected men, with mutations of the TEX11 geneleading to meiosis residue are of the greatest importance.

The importance of other genes such as NR5A1, DMRT1 as a cause of fertility disorders is not entirely clear. In patients without an AZF deletion, the examination of these genes can be discussed as part of a multi-gene analysis using Next Generation Sequencing (NGS).

Genetic analysis may be offered if a rare monogenic spermatogenesis disorder is suspected.

1.2. Obstructive spermatogenesis disorder

In these cases, there is usually intact spermiogenesis in the testicular tissue, so that the chances of success for ART as part of TESE / ICSI are good. About 2% of men with azoospermia have one CBAVD (congenital bilateral aplasia of the ductus deferens) before, more rarely a unilateral expression (CUAVD).

The main cause of ductus deferens aplasia are mutations in the CFTR gene, which is responsible for cystic fibrosis. At least one mutation in the CFTR gene is detected in around 80% of patients with CBAVD.

Since it must be assumed that only homozygosity or compound heterozygosity leads to clinical symptoms, if only one mutation is detected, the complete sequencing of the CFTR gene including the 5-T allele should be carried out. Complete sequencing of the CFTR gene is also useful for clarifying possible risks to children.

Fig. 4: Y chromosome with the azoospermia factor regions AZFa, AZFb and AZFc and their deletion frequencies. Several regions are deleted in around 20% of patients.

There are no Evidence that heterozygosity (frequency in Germany approx. 1:25) causes fertility disorders.

An obstructive spermatogenesis disorder can occur in connection with a malposition of the kidneys, but is then usually not caused by mutations in the CFTR gene.

ADGRG2 gene: In rare cases, mutations in the X-linked ADGRG2 gene can lead to CBAVD.

If obstructive azoospermia is suspected, the CFTR gene should be analyzed after other causes have been ruled out. This should record all relevant pathogenic mutations including the TG-T repeat in intron 8. If a heterozygous mutation is found in this way, a complete sequencing should be carried out. If the CFTR analysis shows normal results in obstructive azoospermia, the ADGRG2 gene should be analyzed.

1.3. Endocrine disorders

1.3.1. Hypergonadotropic hypogonadism

Patients with Klinefelter syndrome have a primary testicular dysfunction, which is the most common genetic cause in up to 15% of men with azoospermia, of which about 80% have a karyotype 47, XXY, and about 20% have higher-grade aneuploids or aneuploids. Mosaics.

In men with hypergonadotropic hypogonadism, a chromosome analysis should be performed after other causes have been excluded.

1.3.2. Hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) has a frequency of 1: 4,000–1: 10,000 and is approximately 3 to 5 times more common in men than in women. The most important gene here is the X-linked KAL1 gene, which is changed in around 10% of patients.

The involvement of other genes such as FGFR1, DAX1, LEP / LEPR, GnRHR, FSHß and LHß is rare, the patients sometimes show additional symptoms. In another part of the patients, several genes are affected (oligogenic inheritance), so that the genetic assignment in individual cases can be difficult. The hormone substitution is symptomatic and does not depend on the gene involved.

In men with congenital hypogonadotropic hypogonadism (CHH), a genetic analysis of CHH genes can be performed after excluding exogenous causes.

Genetic causes of female infertility

2.1. Ovarian failure

Oligo- or amenorrhea is present in around 40% of women with a fertility disorder. The most important factor is age. From age 40, many oocytes are aneuploid.

The primary ovarian failure is through one hypergonadotropic hypogonadism characterized by mostly underlying gonadal dysgenesis (streak gonads mostly without follicles or endocrine-disrupting tissue). About 10% of the women affected have a gonosomal aberration with a 45, X cell line or 47, XXX cell line or a structurally altered X chromosome.

The higher the XX percentage in a mosaic, the greater the likelihood of normal puberty, spontaneous cycles and fertility. If the mosaic percentage of a 45, X cell line is less than 30%, the ovarian function is not significantly restricted. Women with triple X syndrome (47, XXX) have normal fertility and no increased risk of primary ovarian failure. Even with women with one premature ovarian failure gonosomal disorders are increasingly found before the 40th year of life.

In women with hypergonadotropic hypogonadism, a chromosome analysis should be performed after excluding exogenous causes.

The XX Gonadal Dysgenesis with degenerated streak gonads but normal growth. It is a rare, heterogeneous, mostly autosomal recessive inherited disease that can also occur in the context of syndromes (Perrault syndrome or ataxia telangiectasia).

The XY gonadal dysgenesis with a female phenotype are based on structural aberrations of the Y chromosome. Mutations in the SRY gene be detected.

Disorders of steroid hormone synthesis (e.g. cytochrome P450C17) lead to a reduction in glucocorticoids and sex steroids with the result of primary amenorrhea, lack of breast development and increased gonadotropins.

Premutations in the FMR1 gene (CGG repeat lengths of 55–200) often lead to one primary or secondary ovarian failure and if passed on to children, they are very likely to lead to a full mutation (repeat lengths> 200) with an intellectual disability, especially in males (fragile X syndrome), but they are not associated with ovarian insufficiency in females.

Women with primary ovarian failure without a family history have an FMR1 premutation in around 2%, in women with a familial accumulation in up to 10–15% of cases. Other monogenic disorders are very rare and are the subject of research.

In the case of primary or premature ovarian insufficiency, a genetic analysis of the FMR1 gene should be performed after other causes have been excluded.

2.2. Disorders of the hypothalamic-pituitary-gonadal axis

Genetic developmental disorders of the hypothalamus involving the GnRH-secreting neurons lead to hypogonadotropic hypogonadism. Hypo- or anosmia (Kallmann syndrome) is present in approx. 50% due to the involvement of olfactory neurons.

A congenital hypogonadotropic hypogonadism has a frequency of 1 in 30,000 to 40,000 in women. In the meantime, up to 40% of the molecular causes of congenital hypogonadotropic hypogonadism can be explained by mutations in around 20 genes (e.g. GNRHR, FSHB, LEP / LEPR, LHB, FGFR1). The contribution of each individual gene is approx. 1–2%, digenic effects are not uncommon (up to 10%).

In women with congenital hypogonadotropic hypogonadism (CHH), a genetic analysis of CHH genes can be performed after excluding other causes

2.3. Hyperandrogenemia

Adrenogenital Syndrome (AGS) is the most important cause of hyperandrogenemia. The most common form is autosomal recessive 21-hydroxylase deficiency with mutations in the CYP21A2 gene. Treatment depends on the genetic defect. Prenatal therapy in suspected compound heterozygous or homozygous AGS in children requires careful diagnosis.

If AGS is suspected, genetic diagnostics should be carried out.

3. Causes that can affect both sexes

3.1. Balanced chromosomal disorders

In men who had undergone ICSI treatment, the incidence of balanced translocations and inversions, which may be associated with increased childhood risks, was three to four times higher. In women, too, balanced chromosomal disorders are a relevant cause of an unfulfilled desire to have children without any gynecological abnormalities being detected. However, there are also increased rates (factor 2–3) of chromosomal disorders (inversions, balanced TC) in partners of infertile men.

After excluding other causes of infertility, a chromosome analysis of both partners should be performed.

3.2. Syndromic disease patterns

In the context of a larger group of syndromic diseases, fertility disorders, among other things, can be present. Examples are the Kennedy type muscular atrophy, myotonic dystrophy and Kallmann syndrome in males and polyendocrinopathy syndrome in females.


  1. AWMF S2k guideline: Diagnostics and therapy before assisted reproductive medicine treatment, Feb. 2019
  2. Donker, R.B., et al., Chromosomal abnormalities in 1663 infertile men with azoospermia: the clinical consequences. Human Reproduction, 2017; 32: 2574-80
  3. Dul, E.C. et al., Who should be screened for chromosomal abnormalities before ICSI treatment? Human Reproduction, 2010; 25: 2673-2677
  4. Tüttelmann, F. et al. Disorders of spermatogenesis. medical genetics, 2018; 30: 12-20

How is a genetic test arranged?

In the case of a sick person, after extensive information and written consent, a diagnostic genetic analysis can be arranged by any doctor.
Prior genetic counseling is strongly recommended.

»You can find more detailed information on the procedure here

According to the GenDG, predictive or carrier testing in a previously unaffected person may only be initiated after genetic counseling.
The advice may only be given by specialists in human genetics, doctors with the additional designation of medical genetics or the qualification for specialist genetic advice.

If you have further questions, e.g. on specific individual cases, the employees of the LADR human genetics department are available at T: 02361 30 00-201 happy to assist. Appointments for genetic counseling can also be made here.

A Chromomome analysis requires a 5-10 ml heparin blood sample, one molecular genetic analysis a 4 ml EDTA sample, which can be sent to the LADR laboratory center in Recklinghausen together with a declaration of consent.