Unexplained Infertility: Certain Gene Variants Can Cause Serious Health Problems

Unexplained or idiopathic infertility means that medical professionals cannot find the cause of the fertility problems. About 17 percent of all women with unexplained infertility have gene variants known to cause diseases, from common conditions like heart disease to rare problems like ALS.

This is what researchers at the Medical College of Georgia report. Their study appears to be the first to identify an increased prevalence of disease-causing genetic variants in women with unexplained infertility. They hypothesized that genetic diseases create a predisposition to infertility and subsequent diseases, and their results support this association. For example, it has been found that women with infertility have an increased risk of cardiovascular disease.

Genes Linked to Unexplained Infertility Can Cause Heart Disease and Cancer

The association with disease was known, but what was not clear; whether there was a genetic link. The researchers sequenced the exomes, which contain the protein-coding gene regions, of 197 women aged 18 to 40 with unexplained infertility, a percentage that makes up about 30 percent of all infertile women, to look for variants in genes that are known or have not suspected of causing disease. Information about the women comes from the AMIGOS process of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Cooperative Reproductive Medicine Network, a panel of approximately 900 couples from multiple institutions with no apparent cause of infertility, such as ovulation problems or unhealthy sperm.

The scientists, led by Lawrence C. Layman, MD, a reproductive endocrinologist and geneticist, found that 6.6% of the women they studied had variants in 59 genes described as “medically actionable,” meaning that they are likely to cause conditions like heart disease and breast cancer, but there are lifestyle changes or medical interventions that could eliminate them, or at least reduce their risk. In comparison, approximately 2.5% of the general population has been found to have variants of these genes. Another 10% of women had gene variants known to cause diseases for which little or no action can be taken to alleviate the problem, such as Parkinson’s disease. They found 14 variants of the medically usable genes in 13 of the women, one woman had two variants. The most common were those that contribute to cardiovascular disease and cancer, the two leading causes of death in the western world. These included relatively well-known variants, such as women with variants of BRCA1 and BRCA2 that are associated with a high risk of breast or ovarian cancer. Six women had variants in five genes associated with an increased risk of cardiovascular disease; Factors such as a genetic predisposition to high cholesterol and irregular heart rhythms, which can sometimes be fatal.

Genetic Tests Could Provide Important Information in the Future

In addition, they found 20 variants in 21 other women in genes linked to conditions that are unlikely to be mitigated, such as a dramatically increased risk of developing ALS (amyotrophic lateral sclerosis), a serious motor nervous system disorder, and the kidney-destroying polycystic kidney disease, ultimately requiring a kidney transplant. Overall, about 17% of women with unexplained infertility had variants that are known or suspected to cause future disease. While more studies are needed before taking steps like recommending genetic testing for all women or men with unexplained infertility, this research provides evidence that testing should be considered in the future.

Another area that needs further investigation is whether some of the gene variants could be at the root of both infertility and disease. Currently, the only variants known to researchers that seem to play a role in both are the carcinogenic BRCA 1 and 2, as they are also involved in meiosis, which is important for sperm and egg formation and function. Both are also involved in repairing double-strand breaks in DNA that are linked to ovarian aging and cancer risk. Another is a variant that causes premature menopause, which is known to increase the risk of heart disease because estrogen is thought to be protective of the female cardiovascular system. The researchers hope the new findings will inspire others to investigate further whether the disease-causing variants found in the women are also factors in their infertility.