The genetics of male fertility--from basic science to clinical evaluation

Our understanding of male fertility has increased dramatically over the past several decades, in large part because of advances in technology and the ability to rapidly analyze large quantities of high-resolution genetic data. These research efforts have led to an understanding of some of the genes involved in male fertility and have enabled us to test for defects in these genes that result in infertility in men. However, our understanding of male fertility remains far from comprehensive, and many genes involved in male fertility likely remain to be identified and their mechanisms of action elucidated. This can only be accomplished through continued, persistent investigations using cutting-edge technologies. In this review, we discuss the history of genetic testing and how it applies to male fertility, from the identification of the sex chromosomes at the turn of the century to classification of single-nucleotide polymorphisms that may result in infertility and are the crux of modern genetic analysis. We discuss the genetic testing methodologies traditionally used for genetic assessment of infertile males, including karyotype analysis, sperm fluorescence in situ hybridization, and polymerase chain reaction-based testing for Y chromosomal evaluation, as well as cutting-edge genetic testing methodologies using microarrays and whole-genome sequencing, permitting analysis at a nucleotide-level resolution. Finally, we describe our vision of the future of genetic testing in the setting of male infertility, culminating in truly personalized medicine for each affected infertile male.