Male Infertility Panel

Infertility is a disorder of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. It affects 10-20% of couples worldwide, with male factor infertility accounting for about half of the cases.

In humans, sexual development and reproductive function occur by the actions of the hypothalamin-pituitary-gonadal axis induced by gonadotropin releasing hormone (GnRH). Aberrations in this axis can lead to pubertal and reproductive deficiencies. Diagnoses of infertility include hypogonadotropic hypogonadism, hypergonadotropic hypogonadism, and obstructive disorders (Layman. 2002. PubMed ID: 11897813). Male patients with hypogonadotropic hypogonadism often present a prepubertal testicular volume of less than 4 ml, absence of secondary sexual features (facial and axillary hair growth, deepening of the voice), decreased muscle mass, diminished libido and erectile dysfunction due to low serum gonadotropin, follicle stimulating hormone (FSH), and luteinizing hormone (LH; Balasubramanian et al. 2017. PubMed ID: 20301509). Hypergonadotropic hypogonadism in male patients is usually caused by testicular dysfunction (oligospermia, azoospermia, or other abnormalities of sperm morphology or motility).

Infertility is a multifactorial complex condition with highly heterogeneous phenotypic representation. Genetic abnormalities, including both chromosomal and single gene alterations, can account for 15-30% of male factor infertility (Hotaling. 2014. PubMed ID: 24286764). Genetic causes can be detected in all major etiologic categories of male infertility (pre-testicular, testicular, and post-testicular forms). Genes and genomic regulation involved in male sexual development (SRY), testicular development (GATA4, NR5A1, NR0B1, WT1, DAX1, SOX9, ARX, ATRX), male genital tract development (AMH, AMHR1, AR, BMP4), and spermatogenesis (AURKC, SPATA16, DAZ, CFTR) have all been associated with male infertility (Miyamoto. 2015. PubMed ID: 26178295). Autosomal dominant, autosomal recessive, and X linked inheritance have been observed in male infertility genes.

Y chromosome microdeletion is the most common genetic cause of male infertility. For this reason, genetic testing to detect Y chromosome microdeleletions is strongly recommended in the case of a male patient with infertility. Please see our Y chromosome deletion analysis (test code 3740) if testing is desired. Sex chromosome aneuploidy, structural abnormality, and copy number variants (CNVs) are also common genetic causes of male infertility, and our CNV analysis enables these large cytogenetic abnormalities as well as some exon-level CNVs to be identified from NGS data.

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants. 

This multi-gene panel analyzes genes involved in both syndromic and non-syndromic male infertility (Baxter. 2015. PubMed ID: 25383892). The detection rate of this NGS panel in a large cohort of infertile male patients is unavailable in the literature. However, in patients with hypogonadotropic hypogonadism, 40-50% of patients have pathogenic variants in 28 genes in this panel.

At this time, the clinical sensitivity of Copy Number Variant (CNV) testing is difficult to estimate due to the lack of large cohort studies. So far, CNVs have been reported in SOX3, LHCGR, SRY, NR0B1, DMRT1, NR5A1, GATA4, WT1, WNT4, and FGFR2.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.1% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).