Genetic Testing

50% of male factor infertility is unexplained.
However because of an increasing understanding of the genetics involved in infertility, more answers are found at a genetic level.

Changes in DNA can result in defective sperm production or maturation. Specific genes or chromosomal¹ abnormalities can be tested in order to explore whether there are genetic factors involved. Our genes can also tell us if we carry certain recessive traits likely to affect our offspring.

Infertile men have a higher incidence of genetic abnormalities than the general population.
Approximately 15 → 20% of azoospermic² and 5 → 10% of oligozoospermic³ males have known genetic abnormalities.
The most common type of karyotype⁴ abnormality associated with infertility is Klinefelter’s Syndrome⁵.
The most frequent chromosomal alteration is Y-chromosome long arm micro-deletions.
For males with azoospermia or oligozoospermia approximately 9.3% have mutations in the CFTR gene⁶ (Cystic Fibrosis Transmembrane conductance Regulator) which can lead to Cystic Fibrosis (CF).

Genetic testing is a type of medical test that identifies changes in genes, chromosomes or proteins. Results confirm whether a suspected genetic condition is present or absent. Genetic testing can also examine a person’s chance of developing a genetic disorder or determine the likelihood of offspring manifesting the condition.

Tests include:
  1. Chromosome Analysis (Karyotype Analysis)
  2. Y-chromosome Micro-deletion Analysis
  3. Cystic Fibrosis Screening
  4. Carrier Screening

Note: Genetic tests are tailored to meet a patient’s specific needs.

1) Chromosome Analysis

There are three main chromosome or karyotype anomalies found in azoospermic or oligozoospermic men.
These include Klinefelter's Syndrome, 46 XX male syndrome and other Y-chromosome macroabberations.

• Kleinfelter's syndrome is one of the most common genetic conditions found in infertile males and occurs in 1:500 male births.
It is estimated to affect 7-13% of Azoospermic men.
If a person has two X-chromosomes then they are female i.e. XX.
If a person has one X-chromosome and one Y-chromosome then they are male i.e. XY.
In a male with Klinefelter’s Syndrome this becomes XXY.
Men with Klinefelter’s Syndrome carry an extra X-chromosome in their genetic make-up.
The effect of Klinefelter’s Syndrome can vary and some men might not develop signs and symptoms. Men can go undiagnosed until they are adults.
Klinefelter’s Syndrome can result in smaller than normal testicular growth and men with this condition produce fewer sperm or are azoospermic. They may also have reduced body hair, less muscle mass and enlarged breast tissue.

• 46XX male syndrome occurs when the testes determining factor (SRY gene) is moved from the Y-chromosome to the X-chromosome during conception, and this X-chromosome is passed to the offspring. This gene is responsible for a normal male external phenotype but as it is alone on an X-chromosome, there would be no genes present for sperm generation.

• Y-chromosome macroabberations are seen in a karyotype as truncated Y-chromosomes, ring Y-chromosomes and isodicentric Y-chromosomes.

2) Y-chromosome Micro-deletion Analysis

The Y-chromosome contains 60 millions DNA bases. It is divided into a short and a long arm. Most deletions which affect male infertility are found in the long arm of the Y-chromosome, in a region called the ‘AZF’ (Azoospermic Factor). Analysis of this region at a finer resolution than karyotyping, allows a patient to discover what exact genes involved in sperm generation have been affected and what are the chances of recovering sperm.
If a deletion is in the AZFa region then the chance of sperm recovery from the testes is extremely poor.
Certain forms of AZFb deletions have a lower chance of sperm being found in the ejaculate or testicular tissue.
An AZFc microdeletion is found in 1:4000 men. These men have a 70% chance of sperm being found in testicular tissue.

It is recommended that if a Semen Analysis, sperm concentration, result is lower than 5million/ml, then Y-chromosome microdeletion analysis should be arranged.

3) Cystic Fibrosis

Cystic Fibrosis (CF) is Irelands most commonly inherited life-threatening disorder. Irelands island population has increased the incidence of this disease. CF is caused by mutations in the CFTR gene. This gene is responsible for the production of a protein that transports ions across cell membranes.
There are two copies of the CFTR gene in a persons genetic make-up.
If both copies carry a mutation then the person has CF.
If only one copy has a mutation and the other is normal, then the the person is said to 'carry' a defective copy of the CFTR gene. These individuals can sometimes manifest CF symptoms. Approximately 1 in 19 Irish people are carriers of a defective CFTR gene.

Cystic Fibrosis affects cells that produce mucus, sweat and digestive juices. Normally, these secretions are thin and slippery, but in cystic fibrosis, a defective CFTR gene (which affects the movement of ions and therefore water across cell membranes) causes secretions to become thick and sticky. These secretions can plug-up tubes, ducts and passageways. The lungs, pancreas, liver, intestine and reproductive system become damaged and a person with CF can suffer repeated chest infections, malnutrition and infertility.

Different DNA mutations can affect the CFTR gene. Some DNA mutations are more severe then others. A mild mutation may result in an absence of sperm ducts (vasal aplasia) without any other obvious defect.
Some men will not be aware they carry a defective CFTR gene until they attempt to conceive a child, at which point they discover the ducts of their reproductive system have not developed properly.

When two carriers of defective CFTR genes, try to conceive a child, then the offspring of that relationship has a 1 in 4 chance of being born with Cystic Fibrosis.

The CFTR gene can be subject to various degrees of testing. An additional CFTR Intron 8 Poly-T Analysis involves testing a region of the gene that does not code for protein but is associated with CBAVD (Congenital Bilateral Absence of the Vas Deferens), mild respiratory symptoms, or idiopathic pancreatitis. When a specific sequence of Intron 8 DNA is found on the same chromosome as a more mild CF mutation, then this can worsen its phenotypic effect.

4) Carrier Screening

Carrier screening, involves identifying unaffected individuals who carry one copy of a gene for a genetic disorder that requires two copies for the disease to be expressed (autosomal recessive inheritance). It is offered to individuals with a family history of a genetic condition or to ethnic groups with a prevalence for a particular condition. Because these conditions are rare, these tests are not carried out routinely by Fertility Check, but can be arranged privately.

Some genetic disorders that can be carried by a person but not manifest symptoms are listed below. Should two unaffected carriers, for a particular disorder, try to conceive a child then there is a 25% chance their child will manifest the condition. There is a 50% chance that their offspring will also be a carrier and a 25% chance they might be completely normal.

  • Bloom's Syndrome
  • Dubin-Johnson syndrome
  • Fanconi anemia
  • Galactosemia
  • Haemochromatosis types 1-3
  • Homocystinuria
  • Pendred syndrome
  • Phenylketonuria
  • Rotor syndrome
  • Tay-Sachs disease
  • Thalassemia
  • Wilson's disease
  • Xeroderma pigmentosum

Note: It’s important to keep in mind that:

  • There are not yet tests available for all diseases or conditions.
  • If a test indicates the presence of a specific mutation, it does not mean that a particular condition will develop but that your chances of it developing are higher.
  • Should a test indicate that a specific mutation is not present it does not mean that a similar condition will not develop e.g. a different form of the same cancer.

¹ A Chromosome is a threadlike structure found within cells that packages our hereditary material (DNA).
² Azoospermic infers an absence of sperm in the ejaculate.
³ Oligozoospermia refers to a concentration of spermatozoa in the ejaculate, below the WHO lower reference limit.
⁴ A Karyotype profiles the number, size and shape of chromosomes in a person’s cells.
⁵ Klinefelter’s Syndrome is a condition in which human males have an extra X chromosome.
⁶ The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene encodes an important membrane protein that regulates the transport of ions and movement of water across epithelial cell membranes. Mutations in this gene can cause Cystic Fibrosis.

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  1. Yoshida, A., Miura, K., Shirai, M., (1996) Chromosome abnormalities and male infertility. Assisted Reproduction Review, 6: 93-100.
  2. Dohle, G., Halley, D., Van Hemel, J., Van den Ouwel, A., Pieters, M., Weber R., & Govaerts L. (2002) Genetic risk factors in infertile men with severe oligozoospermia and azoospermia. Human Reproduction Vol. 17, No.1 pp. 13-16.

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