Contemporary genetics-based diagnostics of male infertility

ABSTRACT

Introduction Thousands of genes are implicated in spermatogenesis, testicular development and endocrine regulation of testicular function. The genetic contribution to male infertility is therefore considerable, and basic and clinical research in the last years found a number of genes that could potentially be used in clinical practice. Research has also been pushed by new technologies for genetic analysis. However, genetic analyses currently recommended in standard clinical practice are still relatively few.

Areas covered We review the genetic causes of male infertility, distinguishing those already approved for routine clinical application from those that are still not supported by adequate clinical studies or those responsible for very rare cause of male infertility. Genetic causes of male infertility vary from chromosomal abnormalities to copy number variations (CNVs), to single-gene mutations.

Expert opinion Clinically, the most important aspect is related to the correct identification of subjects to be tested and the right application of genetic tests based on clear clinical data. A correct application of available genetic tests in the different forms of male infertility allows receiving a better and defined diagnosis, has an important role in clinical decision (treatment, prognosis), and allows appropriate genetic counseling especially in cases that should undergo assisted reproduction techniques.

KEYWORDS:

• azoospermia
• genetics
• Klinefelter
• male infertility
• Y microdeletion

Article highlights

• The genetic contribution to male infertility is high and research in last years found a number of genes that could potentially be used in clinical practice. However, genetic tests currently recommended in routine clinical practice are still relatively few.

• Genetic causes of male infertility vary from chromosomal abnormalities to copy number variations (CNVs), to single-gene mutations.

• Azoospermia and severe oligozoospermia (<10 million total sperm/ejaculate) caused by primary testicular damage should be tested for karyotype anomalies and Y chromosome long arm deletions.

• Hypogonadotropic hypogonadism should be tested for candidate genes by a panel including multiple genes.

• Congenital bilateral or unilateral absence of vas deferens should be tested for CFTR gene mutations.

• Azoospermia and severe oligozoospermia with signs of androgen insensitivity (high LH, high/normal testosterone) should be tested for androgen receptor gene mutations.

• Studies suggested that idiopathic forms also with moderate oligozoospermia could be tested for the gr/gr deletions in the Y chromosome.

• Rare causes of male infertility (spermatocytic arrest, isolated idiopathic complete asthenozoospermia, globozoospermia, macrocephaly, history of cryptorchidism) could be tested for specific gene mutations (TEX11, dynein genes DNAI1, DNAH5, DNAH11, DPY19L2, AURKC, NR5A1, INSL3, and RXFP2, respectively).

• Pharmacogenetic tests for FSH treatment of male infertility are promising but not yet applicable routinely on clinical practice.

• A correct application of available genetic tests in the different forms of male infertility allows receiving a better and defined diagnosis, has an important role in clinical decision (treatment, prognosis), and allows appropriate genetic counseling especially in cases that should undergo assisted reproduction techniques.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.