What are the genetic causes of male infertility?

Chromosomal abnormalities in males, such as translocations and inversions, which can be found with routine karyotyping, are found in approximately 1% of azoospermic males. However, the most common chromosomal abnormalities in azoospermic men are abnormalities involving the sex chromosomes, which are found in approximately 4% of these men. Klinefelter’s syndrome, in which patients show a 47,XXY karyotype, is the most frequent form. Even in these cases, we can usually find a few rare sperm adequate for fertility using ICSI.

However, the percentage of male infertility that can be explained by karyotyping alone is low, this being mainly due to the low resolution of routine cytogenetic studies. It was not until the development of modern molecular techniques such as polymerase chain reaction (PCR) that we could study the genetic causes of male infertility with much greater detail. Since then, many more genetic abnormalities, such as micro-deletions and point mutations, have been described in infertile males, with most research focusing on the role of genes on the human Y chromosome. We have shown that the long arm of the Y chromosome contains not one but many distinct deletion intervals and at least 60 genes belonging to nine gene families whose exclusive function is in spermatogenesis.

In fact, the deletion frequency of one or more of these regions on the Y chromosome in men with azoospermia or severe oligozoospermia is approximately 15% (Figure 1). After our initial report, many laboratories throughout the world have reported on these sub-microscopic deletions of the Y chromosome in azoospermic and severely oligozoospermic men. In fact, deletion screening of the Y chromosome is now considered standard practice for severely oligozoospermic and azoospermic patients undergoing assisted reproduction in most countries in the world.