Clinical genetic testing for male factor infertility: current applications and future directions

Abstract

Spermatogenesis involves the aggregated action of up to 2300 genes, any of which, could, potentially, provide targets for diagnostic tests of male factor infertility. Contrary to the previously proposed common variant hypothesis for common diseases such as male infertility, genome-wide association studies and targeted gene sequencing in cohorts of infertile men have identified only a few gene polymorphisms that are associated with male infertility. Unfortunately, the search for genetic variants associated with male infertility is further hampered by the lack of viable animal models of human spermatogenesis, difficulty in robustly phenotyping infertile men and the complexity of pedigree studies in male factor infertility. In this review, we describe basic genetic principles involved in understanding the genetic basis of male infertility and examine the utility and proper clinical use of the proven genetic assays of male factor infertility, specifically Y chromosome microdeletions, chromosomal translocations, karyotype, cystic fibrosis transmembrane conductance regulator mutation analysis and sperm genetic tests. Unfortunately, these tests are only able to diagnose the cause of about 20% of male factor infertility. The remainder of the review will be devoted to examining novel tests and diagnostic tools that have the potential to explain the other 80% of male factor infertility that is currently classified as idiopathic. Those tests include epigenetic analysis of the spermatozoa and the evaluation of rare genetic variants and copy number variations in patients. Success in advancing to the implementation of such areas is not only dependent on technological advances in the laboratory, but also improved phenotyping in the clinic.

Implication of sperm chromosomal abnormalities in recurrent abortion and multiple implantation failure

“…Direct genetic testing of spermatozoa consists of assessment of chromosome aneuploidy or alternatively the evaluation of spermatozoa for the level of single and double-strand DNA breaks, known as DNA fragmentation analysis (Hotaling and Carrell, 2014). In this article, the focus is on FISH technology, the most frequently used method for cytogenetic analysis of spermatozoa, although it still has some limitations, as it only permits the screening of a limited number of chromosomes due to the reduced number of DNA probes available.…”

Limitations of semen analysis as a test of male fertility and anticipated needs from newer tests

“…At this stage, genetic testing should have been done and counseling if necessary should have been provided to the coupleFuture sperm function tests need to accurately predict the success of fertilization in vitro and whether the progeny will be healthy. This may include using epigenetics and deep sequencing studies for clinical diagnosis of male infertility to discover spermatozoal epigenetic disorders (53–55), spermatozoal small noncoding RNA defects (56, 57) and other subtle genetic abnormalities that may impact fertilizing potential and the outcome of the progeny (58). …”

Meiotic Nondisjunction: Insights into the Origin and Significance of Aneuploidy in Human Spermatozoa

“…Moreover, despite widespread usage of standardized WHO guidelines, it remains a relatively subjective analysis (Lewis 2007 ). Therefore, despite our ability to measure altered semen parameters and extensive research to establish the genetic causes and identify clinically relevant biomarkers, the underlying etiology of the vast majority of male factor infertility (up to 80 %) is classifi ed as idiopathic (Hotaling and Carrell 2014 ). Nevertheless, it seems plausible that the majority of idiopathic male factor infertility will be associated with as of yet unknown genetic factors; therefore, there is a requirement to identify these factors and develop clinically relevant tests.…”