Approximately 15% of couples in western countries have infertility problems. Identification of genetic alterations responsible for infertility is important for therapy and to avoid transmission of genetic abnormalities that could impair the health of offspring, especially for couples with idiopathic infertility and those undergoing assisted reproductive techniques (ART). The aim of this review is to summarize the main genetic tests to offer to infertile couples during diagnostic work-up and in cases of ART, considering future directions of risk assessment in the field of reproductive medicine. Before offering a genetic test to an infertile couple, it is crucial to characterize their clinical and hormonal profile. Genetic testing should only be carried out when appropriate, that is when clinical and family history suggest a genetic cause of infertility. The genetic tests to offer to infertile couples must be targeted at infertility and should always consider the cost/benefit ratio. No causative genes have been identified for certain conditions, making clinical genetic testing impractical. Next generation sequencing (NGS) is a powerful tool for the identification of pathological mutations and for discovering new disease-associated loci in the field of reproduction. Comprehensive multigene panels for infertile risk assessment could simplify the diagnostic and therapeutic process. The main limitation is interpretation of the enormous amount of NGS data, since the clinical role and biological implications of variants, especially those of unknown significance, are still unclear.
1. Stuppia L, Gatta V, Antonucci I, Giuliani R, Scioletti AP, Palka G. Genetic testing in couples undergoing assisted reproduction technique protocols. Expert Opin Med Diagn. 2009 Sep;3(5):571-83.
2. Aksglaede L, Link K, Giwercman A, Jørgensen N, Skakkebaek NE, Juul A. 47,XXY Klinefelter syndrome: clinical characteristics and age-specific recommendations for medical management. Am J Med Genet C Semin Med Genet. 2013;163C:55-63.
3. Song SH, Chiba K, Ramasamy R, Lamb DJ. Recent advances in the genetics of testicular failure. Asian J Androl. 2016 May- Jun;18(3):350-5.
4. Ferlin A, Arredi B, Speltra E, Cazzadore C, Selice R, Garolla A, Lenzi A, Foresta C. Molecular and clinical characterization of Y chromosome microdeletions in infertile men: a 10-year experience in Italy. J Clin Endocrinol Metab. 2007 Mar;92(3):762-70
5. Giuliani R, Antonucci I, Torrente I, Grammatico P, Palka G, Stuppia L. Identification of the second CFTR mutation in patients with congenital bilateral absence of vas deferens undergoing ART protocols. Asian J Androl. 2010 Nov;12(6):819-26.
6. Hart RJ. Physiological aspects of female fertility: role of the environment, modern lifestyle, and genetics. Physiol Rev. 2016 Jul;96(3):873-909
7. Li Z, Huang Y, Li H, Hu J, Liu X, Jiang T, Sun G, Tang A, Sun X, Qian W, Zeng Y, Xie J, Zhao W, Xu Y, He T, Dong C, Liu Q, Mou L, Lu J, Lin Z, Wu S, Gao S, Guo G, Feng Q, Li Y, Zhang X, Wang J, Yang H, Wang J, Xiong C, Cai Z, Gui Y. Excess of rare variants in genes that are key epigenetic regulators of spermatogenesis in the patients with non-obstructive azoospermia. Sci Rep. 2015 Mar 5;5:8785.
8. Liu X, Li Z, Su Z, Zhang J, Li H, Xie J, Xu H, Jiang T, Luo L, Zhang R, Zeng X, Xu H, Huang Y, Mou L, Hu J, Qian W, Zeng Y, Zhang X, Xiong C, Yang H, Kristiansen K, Cai Z, Wang J, Gui Y. Novel Y-chromosomal microdeletions associated with non-obstructive azoospermia uncovered by high throughput sequencing of sequence-tagged sites (STSs). Sci Rep. 2016 Feb 24;6:21831.
9. Pereira R, Oliveira J, Ferraz L, Barros A, Santos R, Sousa M. Mutation analysis in patients with total sperm immotility. J Assist Reprod Genet. 2015 Jun;32(6):893-902