State of the Art for Genetic Testing of Infertile Men

Intracytoplasmic sperm injection (ICSI) now provides fertility in many cases of severe idiopathic spermatogenic failure and obstructive azoospermia. Genetic causes must be sought by systematic evaluation of infertile men and affected couples informed about the implications of such diagnoses for assisted reproductive technology outcome and their potential offspring. This review discusses established and emerging genetic disorders related to fertility practice. Chromosomal anomalies are found in about 7% men with idiopathic spermatogenic failure, predominantly numerical/structural in azoospermic men and translocations/inversions in oligospermic men. Routine karyo-typing of men with sperm densities less than 10 million/ml, even in the absence of other clinical presentations, is recommended because infertility is associated with higher rates of aneuploidy in ejaculated or testicular sperm and increased chromosomal defects in ICSI offspring. The long arm of the Y chromosome microdeletions are the most common recognized genetic cause of infertility and are found in about 4% men with sperm densities less than 5 million/ml. Routine testing using strict quality assurance procedures is recommended. Azoospermia factor (AZF)-c deletions, the most common form of the long arm of the Y chromosome microdeletions, are usually associated with low levels of sperm in the ejaculate or in testis biopsies, whereas men with AZFa or AZFb+c deletions usually produce no testicular sperm. When AZF-deleted sperm are available and used for ICSI, fertility defects in male offspring seem inevitable. Bilateral congenital absence of the vas is associated with heterozygosity for cystic fibrosis transmembrane receptor mutations making routine gene screening and genetic counseling of the couple essential. Testing for less common genetic associations/defects linked with different reproductive dysfunction may be applicable to specific patients but have not entered routine practice. (J Clin Endocrinol Metab 95: 1013-1024, 2010)