Phosphorus Research: Enrichment of Genetic Variants Related to Infertility in Females Seeking Fertility Treatment
Last week, Phosphorus attended the Pacific Coast Reproductive Society (PCRS) annual conference in Palm Springs, Florida — an event offering appreciable opportunity for industry professionals to present and absorb developments in reproductive science and clinical care. Phosphorus was proud to present its scientific poster, entitled “Enrichment of Genetic Variants Related to Infertility in Females Seeking Fertility Treatment.” The poster framed results from our study on rates of genetic mutation in candidate genes that impact four infertility conditions: ovarian hyperstimulation syndrome (OHSS), polycystic ovarian syndrome (PCOS), recurrent pregnancy loss (RPL), and premature ovarian insufficiency (POI). Because infertility is a public health problem that affects 12% of women, our goal was to provide insight into the creation of a genetic diagnostic panel to evaluate these four conditions. [To view the poster, scroll to the bottom of the article.]
After a detailed review of existing literature, we generated a comprehensive list of genes that either are strongly associated with one or more of the above infertility conditions or have been linked less definitively to one of them (referred to as “tier 1” and “tier 2,” respectively). Our cohort consisted of 7,403 consented female research patients, who either received carrier screening as part of their treatment at fertility centers or via their OB/GYN. These patients’ data were compared with the Exome Aggregation Consortium’s (ExAC) data set as a control, and both sets were limited to patients reporting European ancestry (Phosphorus) or non-Finnish European descent (ExAC), due to the mostly European makeup of our dataset.
Forty-five fertility-related genes from our panel were evaluated to determine whether the frequency of curated, disease-associated mutations in our database was enriched compared to the frequency of those alleles in the ExAC dataset. One variant of interest, F2 c.*97G>A, did not appear in the exome sequencing of ExAC, nor in the newer Genome Aggregation Database (GnomAD) data sets (from which Phosphorus looked at non-Finnish European whole genome sequencing). Chi-square test with Yates’ correction was used to determine statistical significance in the comparison of allele frequencies.
While we did not detect enrichment of disease-associated variants over our entire set of genes and variants, our cohort is enriched for certain genetic variants that may contribute to infertility. Significant enrichment was observed in our cohort for five variants in F11 (c.901T>C;p.F301L), CFTR (c.1865G>A;p.G622D), and HBB (c.20A>T;p.E7V, c.92+1G>T, and c.19G>A;p.E7K). Additionally, by comparing to the whole genome sequencing control from GnomAD, significant enrichment of the F2 c.*97G>A mutation (p<0.01) was detected (Table 1). At the whole gene level, disease-associated variants were enriched overall in F11 (p<0.01), HBB (p<.001), and CYP21A2 (p<.001) (Table 2). Inclusion of the F2 c.*97G>A variant would show enrichment in F2 as well (p<0.0001).
Enrichment in several genes involved in thrombosis and RPL was observed in our cohort, emphasizing the role of genetics when assessing infertility. This finding underscores the importance of research to develop genetic tests that inform medical decision-making in fertility.