Genetic disorders can contribute to fertility issues for both men and women. Genetic testing can identify mutations that lead to conditions like Klinefelter syndrome, fragile X syndrome or Kallmann syndrome that require medical treatment.
Typically, this form of testing involves the examination of long strands of DNA called chromosomes. A blood test known as karyotype can help assess how they have been assembled or structured.
1. Identifying the Cause
Genetic mutations play an integral part in many infertility cases, with our understanding of fertility-related genes continually expanding. Unfortunately, however, it can be challenging to pinpoint individual patient cases by their genetic variants.
One method involves identifying single gene mutations known to lead to infertility-related phenotypes, such as Klinefelter syndrome or Y chromosome deletions, with an easy blood test. Or alternatively, some inherited conditions that interfere with fertility can be identified using a saliva test.
However, this approach is limited since many more genes may contribute to infertility-related phenotypes and only a minority of mutations within them are responsible for idiopathic infertility. Furthermore, every individual carries thousands of minor alleles (such as nonsynonymous SNPs or NSPs) of unknown significance (NSP).
Given these restrictions, the optimal solution for identifying genes involved in idiopathic infertility is using whole exome or genome sequencing approaches to screen for Mendelian trait-causing variants. Unfortunately, this process can be both time consuming and expensive, thus it is necessary to prioritize potential infertility genes using practical criteria (e.g. Mendelian effect genes). This can be accomplished using existing resources such as Ensembl or gnomAD databases or in-silico prediction packages such as SIFT/Randolph.
2. Developing a Treatment Plan
Genetic testing to pinpoint the source of infertility can provide doctors with a plan for treatment. For instance, women who carry mutations that make them twice as likely to experience miscarriages could work with their healthcare team to reduce the risk by having more frequent sex closer to her period. Furthermore, genetic tests can help physicians identify whether assisted reproductive techniques might be successful treatments.
Men seeking genetic testing may benefit from genetic analysis to detect conditions that interfere with their sperm production or motility. A common approach is using conventional Karyotype Analysis (KA), which employs G-banding to visualize lymphocyte chromosomes from peripheral blood samples. Although effective, this technique has some drawbacks as it’s less sensitive in detecting abnormalities than others such as FISH testing or DNA-seq tests.
Male infertility may be caused by genetic disorders with known causative mutations that can be detected with modern targeted genetic tests. A molecular diagnosis can assist with assisted reproductive technology selection as well as direct antenatal screening procedures.
While it’s vitally important to gain clarity on the causes of infertility, creating a comprehensive treatment plan is equally crucial to alleviate stress during treatments and alleviate feelings of hopelessness if these fail. If nothing else works out naturally for you, consider other avenues like donor eggs/sperm or adoption as potential ways of building your family if natural conception fails you.
3. Preventing Future Pregnancies
Many of the symptoms associated with infertility can be linked to genetic disorders that interfere with key reproductive processes, and once identified treatment can begin immediately to improve fertility outcomes and help couples plan better for assisted reproductive technologies. Furthermore, genetic testing provides couples with information that may help them plan better.
Next-Generation Sequencing (NGS) technology enables targeted tests to detect infertility caused by chromosomal abnormalities with pinpoint accuracy and sensitivity compared to prior gene arrays at one-fifth the cost, making NGS ideal for identifying causative mutations among infertile patients with infertility caused by rearrangements or variants related to clinical phenotype.
Tests could include Klinefelter syndrome or Turner syndrome for men, both of which can impair sperm production and prevent it from traveling down the vas deferens, blocking conception. For women, this could include testing for BRCA1/BRCA2 gene mutations which increase risk for breast cancer development while decreasing chances of conception (92).
NGS may not yet be capable of diagnosing all genes linked to infertility, but advances in this field could make this possible in the future. A recent genetic test developed by Celmatix using NGS screens for more than 350 genes linked with male fertility; currently available through reproductive specialists but soon planned to be offered directly to patients who have tried unsuccessfully (92).
4. Increasing Your Chances of Conception
Infertility can be a complex issue and its causes vary widely, yet genetic testing can be an invaluable asset in understanding your risk and finding your pathway to pregnancy. At Genome Medical, genetic counselors can help assess risk and recommend tests which could increase chances of conception.
Genetic mutations rarely lead to isolating infertility; more often genetic disorders play a part. While karyotype analysis remains an integral component of female infertility assessment, targeted multigene panels provide patients with another cost-effective option and may deliver faster results than whole chromosome testing.
Celmatix, a new company offering fertility care, has developed a DNA test which claims to predict whether women will suffer recurrent miscarriages or be unable to conceive at all.
Problematically, such predictions are inaccuracy and often inaccurately represent actual risks and may even be misleading. A report that a woman receives may say, for instance: “Despite your high risk of miscarriages, genetic variants do not contribute directly.” However, such information lacks key context: for instance it might not include that frequent miscarriages are much more prevalent among those with certain genetic conditions like Klinefelter syndrome or AZF deletions.
