Genetic Causes of Infertility
Infertility is defined as the inability to conceive after twelve months of unprotected intercourse (six months for women over age 35) and affects approximately 10%-15% of all couples. Common causes of infertility include ovulatory dysfunction, damaged or blocked fallopian tubes, endometriosis, male factor infertility, and diminished ovarian reserve (DOR). However, there are also genetic causes infertility which can result from either the impaired functioning of a specific gene or from chromosome abnormalities. Genes are segments of DNA that provide our bodies with the instructions they need to work properly, while chromosomes are the structures that hold all of our genes and should be present in the cells of our body is a very specific number (46 chromosomes total in 23 pairs).
The most common genetic causes of infertility include:
Klinefelter syndrome is a genetic condition in which a male is born with an extra copy of the X chromosome (XXY instead of XY). People with Klinefelter syndrome typically have tall stature, small testes, reduced muscle mass, reduced body and facial hair, as well as enlarged breast tissue. They may also have language delay and cognitive deficiencies. In addition, azoospermia (no sperm identified in the ejaculate) or oligospermia (a reduced sperm count in the ejaculate) is detected in many Klinefelter patients, resulting in infertility.
Turner syndrome is a genetic condition in which a female has only one X chromosome present instead of two; the other X chromosome is typically either missing or structurally altered. Common features of Turner syndrome include short stature, congenital heart defects, nonverbal learning disabilities, and behavioral/psychological issues. Less commonly, conductive hearing loss, thyroid problems, minor skeletal anomalies, lymphedema, a webbed neck, and kidney anomalies have been observed. Turner syndrome also compromises fertility in many affected individuals via either gonadal dysgenesis (failure of the ovaries to properly develop) or an early loss of ovarian function (premature ovarian insufficiency, or POI) due to the loss of genes on the X chromosome that are crucial to normal ovarian development and function.
A Y-microdeletion is when there is a small missing segment of the Y chromosome. The Y chromosome holds the genes responsible for male sexual development and the production of sperm. If a portion of these genes are missing (deleted), the normal production of sperm may be significantly impacted, resulting in infertility due to either azoospermia or oligospermia.
Balanced Chromosome Translocations
Translocations are the exchange of segments of genetic material between chromosomes that are not in the same pair. Translocations are considered “balanced” when the exchange has been equal (ie. no genetic material is lost or gained overall). Carriers of balanced translocation are typically healthy because they have the correct amount of genetic material – it is just in a different order. However, the rearrangement of chromosome material results in problems during the production of egg or sperm cells (a process called meiosis), which leads the creation of a large percentage of egg or sperm cells with extra or missing chromosome material. Having extra or missing chromosome material is often incompatible with life, so balanced translocation carriers (both male and female) often experience unexplained difficulty conceiving and/or recurrent pregnancy losses. In addition, men with balanced translocations also have an increased risk of infertility related to oligospermia or azoospermia.
Fragile X Premutation
Fragile X syndrome is a genetic disorder characterized by significant intellectual disabilities, cognitive impairment, and characteristic physical features such as a long, narrow face and large ears. It is caused by an increased number of CGG repeats (a portion of genetic code) at the beginning of the FMR1 gene, which is a gene essential to normal brain function. While most individuals have less than 45 CGG repeats, individuals with full Fragile X Syndrome have more than 200 CGG repeats. Premutation carriers have between 55-200 CGG repeats and do not show symptoms of Fragile X Syndrome. However, female carriers are at risk for having children with Fragile X Syndrome if expansion from the permutation range to >200 repeats occurs in their offspring; this is more likely the higher the number of CGG repeats present. Female premutation carriers also have an increased likelihood of infertility related to Premature Ovarian Insufficiency (POI), which is associated with significantly decreased ovarian reserve, irregular menstrual cycles, and early menopause (before age forty). In addition, male premutation carriers (and a small percentage of females) are at an increased risk of Fragile X Tremor/Ataxia Syndrome (FXTAS) later in life, which presents similarly to Parkinson Disease.
Cystic fibrosis is a genetic condition that results from improper or absent functioning of the CFTR gene. This gene is crucial for the normal transport of chloride and bicarbonate ions in our cells, and when it is not working properly thick and debilitating mucus accumulates in many important organs. This results in several forms of morbidity and mortality, which are most commonly associated with disease of the lungs, pancreas, and gastrointestinal tract of varying severity. However, the reproductive tract can also be negatively impacted, resulting in infertility. Women with Cystic Fibrosis are often infertile due to thickened cervical mucus, disruption of the uterine environment, delayed puberty, and ovulatory dysfunction. Men with Cystic Fibrosis are frequently azoospermic due to Congenital Bilateral Absence of the Vas Deferens (CBAVD). CBAVD results in infertility because while sperm is still produced by the testes, without the vas deferens it cannot be transported to the urethra, resulting in a form of infertility known as obstructive azoospermia.
Congenital Adrenal Hyperplasia
Congenital Adrenal Hyperplasia is a genetic disorder characterized by the disruption of steroid hormone production. There are several types but the most common is 21-hydroxylase-deficient Congenital Adrenal Hyperplasia (21-OH CAH), which is associated with the CYP21A2 gene. This condition can be seen in two forms, Classic or Non-Classic. The classic form of the condition is characterized by ambiguous genitalia in females (due to significant excess of androgens, or male sex hormones), adrenal insufficiency, and mineralocorticoid deficiency. Non-classic 21-OH CAH is less severe in presentation and is characterized by elevated androgens in females, which can result in infertility related to ovulatory dysfunction. Women with Non-classic 21-OH CAH may also exhibit symptoms such as hirsuitism (excessive hair growth), acne, and androgenic alopecia (hair loss).
BRCA1 and BRCA2-related Hereditary Breast & Ovarian Cancer Syndrome (HBOC)
BRCA1 and BRCA2 are genes that provide the body with instructions for repairing damaged DNA, which helps protect against the development of certain types of cancer. Individuals with BRCA1 or BRCA2 genes that are not working properly have a higher susceptibility to damaged DNA, leading to an increased risk for specific cancers (particularly breast, ovarian, pancreatic, and prostate). Some studies also suggest that women with BRCA1/2-related HBOC may have an increased risk of diminished ovarian reserve, and may not respond as well to fertility treatment as their age-matched peers. In addition, women with HBOC may be recommended to undergo a surgery called a bilateral salpingo-oophorectomy (BSO) which involves removing the fallopian tubes and ovaries in order to reduce the risk of developing ovarian cancer. This would result in the loss of the ability to conceive with one’s own eggs unless eggs or embryos have been frozen (cryopreserved) prior to undergoing risk-reducing surgery.
Due to the role that genetic conditions play in infertility, your physician may recommend additional genetic tests as part of your initial reproductive evaluation if he/she deems them appropriate (depending on your particular medical/reproductive history). In addition, genetic counseling is available for all RMA of New York patients to discuss genetics-related concerns/questions, to help you understand your genetic testing options and results, and to facilitate informed decision-making regarding your reproductive options.