Genetic abnormalities can cause infertility by affecting sperm production or sperm transport. People with non-obstructive azoospermia or severe oligospermia have an increased chance of having a genetic variation compared to fertile people.

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Definitions: 

Azoospermia: A condition in which there are no sperm in the semen 

CTFR gene: Gene involved in maintaining salt and water in the body. Mutations in this gene are associated with cystic fibrosis 

Epididymis: A tightly-coiled tube that is attached to each of the testes where sperm is stored and matures after being produced in the testes. 

Non-obstructive azoospermia: no sperm in the ejaculate due to failure of sperm production 

Obstructive azoospermia: the absence of sperm in the ejaculate despite normal sperm production 

Oligospermia: A low sperm count;fewer than 15 million sperm per millilitre of semen. Severe oligospermia considered  fewer than 5million sperm/mL semen. 

Vas deferens: A tube that carries sperm from the epididymis to the urethra through a structure called the ejaculatory duct 

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Cystic fibrosis gene mutations

There is a strong association between CFTR mutations and bilateral obstruction of the epididymis / congenital bilateral absence of vas deferens (CBAVD). The prevalence of CFTR mutations is  increased among people with azoospermia related to CBAVD and people with under-developed vas deferens. 

 

Karyotype  chromosomal abnormalities 

People with low or absent sperm count are more likely to have an abnormal karyotype (variation in the number or arrangement of chromosomes). The prevalence of karyotype variation is 10%–15% in azoospermic men, 5% in men with severe oligozospermia, and <1% in men with normal sperm concentrations . Sex chromosomal aneuploidy (Klinefelter syndrome; 47,XXY) accounts for about two thirds of all chromosomal variations observed in infertile men. The prevalence of structural autosomal abnormalities, such as inversions and balanced translocations, is also higher in infertile men than in the general population. Rarely, azoospermic men may be found to have the 46,XX disorder of sexual development resulting from translocation of sex-determining region Y to one of their X chromosomes. When a person with sperm has a significant karyotype abnormality, they are at increased risk for their partner having miscarriages and for having children with chromosomal and congenital variations. Therefore, people with non-obstructive azoospermia or severe oligozospermia are evaluated with a high resolution karyotype before using their sperm to perform ICSI.

More information regarding karyotype: https://www.dranjuagarwal.com.au/karyotype

 

Y-chromosome micro-deletions

Microdeletions of clinically relevant regions of the Y chromosome have been found in 7% of infertile men with severely impaired sperm production, compared with 2% of fertile men. However, the percentage of men with Y-chromosome micro deletions increases to 16% in men with azoospermia or severe oligozoospermia. Such microdeletions are too small to be detected by standard karyotyping, but they can be identified with the use of polymerase chain reaction techniques to analyze sequence tagged sites that have been mapped along the entire length of the Y chromosome. Most deletions causing azoospermia or oligozoospermia occur in regions of the long arm of the Y chromosome. (Yq11) known as the azoospermia factor (AZF) regions. The specific location of the deletion along the Y chromosome influences its effect on spermatogenesis. Many men with a microdeletion in the AZFc region of the Y chromosome have severe oligozoospermia. Others with AZFc region deletions are azoospermic but may still produce sufficient numbers of sperm to allow testicular sperm extraction. Sperm production in such men appears to be stable over time, and the results of ICSI are not affected adversely by the AZFc deletion. In contrast, deletions involving the entire AZFa and AZFb region appear to predict a very poor prognosis for sperm retrieval.

 

Male offspring of individuals with Y-chromosome microdeletions will inherit the abnormality and, therefore, may also be infertile. It is important to note that a negative Y-chromosome microdeletion test result does not necessarily exclude a genetic abnormality, because there may be other, currently unknown, gene sequences on the Y or other chromosomes that also might be required for normal spermatogenesis.

 

Y-Chromosome analysis is offered to people who have non-obstructive azoospermia or severe oligozoospermia before performing ICSI with their sperm.