Female 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 and is generally attributed to males and females equally.

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 hypogonadotrophic hypogonadism, hypergonadotrophic hypogonadism, and obstructive disorders (Layman 2002. PubMed ID: 11897813). Female patients with hypogonadotrophic hypogonadism often present symptoms of estrogen deficiency, such as absent breast development or hypoestrogenic amenorrhea owing to low serum gonadotrophin, follicle stimulating hormone (FSH), and luteinizing hormone (LH); while female patients with hypergonadotrophic hypogonadism manifest symptoms of elevated serum FSH and LH, and ovary defect (primary amenorrhea and premature ovarian failure) (Layman 2013. PubMed ID: 23499866).

Infertility is a multifactorial complex condition with highly heterogeneous phenotypic representation. Genetic abnormalities including both chromosomal and single-gene alterations account for 15-30% of cases of infertility (Hotaling 2014. PubMed ID: 24286764). Pathogenic variants in at least 20 genes cause hypogonadotropic hypogonadism including Kallman syndrome in about 40-50% of patients (Balasubramanian et al. 2017. PubMed ID: 20301509). The two most commonly involved genes are FGFR1 and CHD7. When combined pituitary hormone deficiency includes hypogonadotropic hypogonadism as a feature, PROP1 pathogenic variants are the most common of the six genes involved. For hypergonadotropic hypogonadism, pathogenic variants in 14 genes cause gonadal failure in 15% of affected females. In eugonadal disorders, activating FSHR pathogenic variants have been described in mullerian aplasia (Layman 2013. PubMed ID: 23499866). See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Sex chromosome aneuploidy, structural abnormality, and Copy Number Variants (CNVs) are common genetic causes of female infertility. For this reason, genetic testing to detect large cytogenetic events and CNVs is recommended in the case of a female patient with infertility. Our CNV analysis enables these large cytogenetic abnormalities as well as some exon level CNVs to be identified from NGS data.

This panel typically provides ≥98% 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

This multi-gene panel analyzes genes involved in both syndromic and non-syndromic female infertility (Baxter et al. 2015. PubMed ID: 25383892). The detection rate of this NGS panel in a large cohort of female 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. For woman with hypergonadotropic hypogonadism and especially 46,XX ovarian failure, about 15% of women have pathogenic variants in 14 genes in this panel (Layman 2013. PubMed ID: 23499866).

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, gross deletions or duplications have been reported in SOX3, LHCGR, SRY, NR0B1, DMRT1, NR5A1, GATA4, WT1, WNT4, and FGFR2.