Advanced laboratory services

INTRODUCTION

It is clear that we are now in an era of genetics and genomics, and major strides are being made in understanding the role of DNA and RNA variants in male infertility. The goal of genetic testing is twofold. First and foremost, is the need to identify genetic conditions that could be passed to the offspring through assisted reproductive techniques. Second, is the need to identify genetic conditions that may impact the ability to obtain spermatozoa through retrieval techniques such as microsurgical testicular sperm extraction.

GENETIC TESTS FOR NON-OBSTRUCTIVE AZOOSPERMIA

Karyotype

A karyotype is recommended by the American Urological Association (AUA) and the European Academy of Andrology (EAA) guidelines in all men with a total motile sperm count below 5 to 10 million who are thought to have non-obstructive azoospermia. Klinefelter syndrome (KS), or 47,XXY, has a prevalence of 1 : 600 males and is the most common cause of azoospermia that is currently assignable through the use of existing genetic tools. 46,XX male syndrome (testicular disorder of sex development) is a rare (1 : 20 000) genetic cause of infertility in men who are phenotypically male. The most common cause of 46,XX male syndrome is a translocation of a portion of the Y chromosome that includes the sex-determining region (SRY), a gene that initiates and maintains the male phenotype.

Chromosomal translocations

The role of chromosomal translocations is well established in male infertility. Infertile men are more likely to have spermatozoa and offspring with chromosomal abnormalities such as translocations, inversions and sex chromosomal abnormalities. It is critically important to evaluate chromosomal abnormalities in infertile men as these can lead to miscarriage or recurrent pregnancy loss.

Y chromosome microdeletion testing

Unlike the autosomal chromosomes, which undergo recombination during meiosis, the Y chromosome does not recombine and has had to evolve its own method of maintaining the fidelity of its genetic material. Errors or microdeletions occur when two distinct palindromic segments of the Y chromosome erroneously combine, deleting any of the intervening genetic material. Although most occur de novo, they will be passed on to all male offspring of the proband. The importance of genetic counseling and informed testing in this group cannot be overstated. Despite significant ethnic variability exists, Y chromosome microdeletions are found in 10% of men with non-obstructive azoospermia and 5% of severely oligozoospermic men. 

Spermatozoa chromosome aneuploidy analysis

The relatively low incidence of significant sperm chromosome aneuploidy in the general population of infertile males, as well as the cost associated with the assay, make sperm chromosome aneuploidy testing inadvisable as a screening tool. However, the assay remains an under used tool that may be of benefit to patients with certain pathologies, especially severe morphological defects, known chromosome structural defects, recurrent pregnancy loss and repeated unexplained IVF failure.

GENETIC TESTS FOR OBSTRUCTIVE AZOOSPERMIA  

Congenital bilateral absence of the vas deferens (CBAVD) is found in ALL patients with cystic fibrosis (CF). If a man with CBAVD is found to have a CFTR gene mutation, it is imperative to screen his partner prior to ART to ensure that his wife is not also a carrier. If both partners are carriers of CFTR mutations, pre-implantation genetic diagnosis is vital, as they would have a 25% chance of having a child with CF.

Reference: Hotaling J, Carrell DT. Clinical genetic testing for male factor infertility: current applications and future directions. Andrology. 2014 May;2(3):339-50.