Genetic testing for male infertility is typically considered when other potential causes of infertility have been ruled out. Genetic testing may be recommended in the following situations:
· Low Sperm Count: When a man has an abnormally low number of sperm in his semen.
· Azoospermia: When no sperm are found in semen samples.
· Physical Indicators: When physical characteristics, such as smaller-than-normal testicles, suggest a potential genetic issue.
· Vas Deferens Absence: When the vas deferens (the tube that carries sperm) cannot be detected during a physical examination.
· Recurrent Miscarriages: When couples have experienced multiple miscarriages, as this may indicate a genetic issue affecting fertility.
In these scenarios, genetic testing can help identify underlying genetic factors that may be contributing to infertility.
While most genetic tests for male infertility do not reveal any abnormalities, approximately 15% of men with a low sperm count or no sperm (azoospermia) do test positive for a genetic disorder. Although there are many different genetic tests available, three specific tests are most commonly used for diagnosing male infertility: Karyotype Analysis, Cystic Fibrosis Gene Mutation Testing (CFGMT), Y Chromosome Microdeletion Analysis.
Karyotype Analysis (KA)
Karyotype Analysis (KA) is a technique used to visualize and analyze human chromosomes to identify abnormalities in their number or structure. This is done by stopping cells from dividing at a specific stage and staining them to see the chromosomes under a microscope. KA can detect large chromosomal abnormalities like extra or missing chromosomes and major structural changes.
Genetic testing for male infertility often includes KA to find issues such as Klinefelter syndrome (extra X chromosome), structural abnormalities like translocations and inversions, and 46, XX male syndrome (a rare condition where Y chromosome material is misplaced). These issues can lead to problems like low sperm count or no sperm, impacting fertility.
Results from karyotope analysis indicate that about 5% of male infertility cases are due to chromosomal abnormalities. Naturally, KA has its limitations. One important limitation is its high cost. Additionally, it cannot effectively detect very small mutations.
For detecting small mutations, Fluorescence in-situ hybridization (FISH) technique is used, as it has higher resolution than KA and can examine specific DNA regions and analyze chromosome integrity of sperm. FISH can provide additional information, especially for men with chromosomal abnormalities undergoing assisted reproductive technologies like IVF.
Y Chromosome Microdeletion Analysis.
The Y chromosome microdeletion test examines the Y chromosome for missing genetic information. Y chromosome microdeletions are missing sections of genetic material that are essential for sperm production. Traditional karyotype tests cannot detect these small deletions. Instead, genetics labs use polymerase chain reaction (PCR) techniques to analyze specific sites along the Y chromosome. Most deletions that result in no sperm (azoospermia) or low sperm production (oligospermia) occur in the AZF (azoospermia factor) region of the Y chromosome.
The azoospermia factor region is vital for sperm production and is divided into three sub regions:
AZF-A
AZF-B
AZF-C.
Deletions in these regions result in different clinical outcomes:
· AZF-A deletions: Cause Sertoli cell-only syndrome, leading to nonobstructive azoospermia (no sperm in semen).
· AZF-B deletions: Prevent sperm maturation, also leading to nonobstructive azoospermia.
· AZF-C deletions: In this case, normal sperm is still present, making assisted reproductive technology (ART) a viable possibility.
Approximately 7.5% of oligospermic (low sperm count) and azoospermic men have Y chromosome microdeletions, with higher rates in men with severe sperm deficiencies.
Testing is recommended for men with sperm counts below 5 million/mL (million per milliliter).
Men with Y chromosome microdeletions should know that these deletions will be passed to all male offspring. Therefore, couples considering ART have three main options:
· Proceed with intracytoplasmic sperm injection (ICSI) and accept the risk of infertile male offspring.
· Choose not to use the sperm for conception.
· Use preimplantation genetic testing to select for female embryos (46, XX).
Cystic Fibrosis Gene Mutation Testing (CFGMT)
Cystic fibrosis genetic testing identifies mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This testing involves analyzing DNA obtained from blood cells or cheek swabs.
In men with congenital absence of the vas deferens, there is often at least one mutation in the CFTR gene. Men with congenital absence of vas deferens, as well as those who produce no sperm, and their female partners, are advised to undergo genetic testing for CFTR mutations. This helps assess the risk of passing on CF to their offspring.
Male children born to men with congenital absence of the vas deferens are at an increased risk of also having the condition due to the genetic inheritance pattern. Therefore, understanding the genetic basis through testing allows couples to make informed decisions about their family planning and reproductive options.
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