Role of Genetics in Male and Female Infertility
Reproduction in any species,is a highly complicated process. It involves co-ordination at several different steps. All of these processes are tightly regulated by a number of genes and thereby require the proper functioning of these genes.
Gene is a unit of DNA, present in every human, which is important for the transfer of hereditary traits to children. Abnormality in any of these may lead to various problems including infertility.
Infertility is the inability to achieve pregnancy (technically within 1 year of marriage), assuming regular intercourse between the couple. Childlessness is a serious issue, carrying major negative psychological impact on couples, and social stigma, especially in a developing countries like ours.
The basis of infertility is also varied and involves a complex interplay of several gene products. It has been estimated that nearly 30% of infertility cases are due to genetic defects.
Genetic disease means any abnormality in one’s genetic make up – involving genes or chromosomes (a group of genes). There can be many types of chromosomal abnormalities like a missing piece of a chromosome (deletion), change in the gene’s DNA sequence (mutation), change in the total number of chromosomes (aneuploidy) etc.
Even if pregnancy does happen, chromosomally abnormal embryos often lead to miscarriages or to the birth of babies with physical or mental abnormalities.
Presently only a few genetic abnormalities are considered to be associated with infertility, but in this era of complete human genome mapping, personalized medicine is rapidly coming to the forefront.
While discussing all the genetic diseases here would be futile, let us focus on the most important ones.
Chromosomal abnormalities are detected in up to 20% of infertile men with severe semen defects like azoospermia, and severe oligozoospermia. Some of the common genetic defects that causes male infertility are:-
Klinefelter Syndrome – 47,XXY(normal male is 46 XY) i.e. presence of an extra X chromosome in a male. It is the most common chromosomal aberration detected in up to 14% of infertile patients with azoospermia.
Klinefelter patients show multiple other features like a tall male with less body hair, weak muscles, learning and behavioral problems. There is high risk of chromosomal abnormalities in their children, even if these men manage to father one.
47,XYY Syndrome -This syndrome is rare, but is more common among infertile males. These men with the 47,XYY karyotype (i.e.an extra y chromosome)are otherwise healthy but semen analyses is usually abnormal.
Structural Chromosomal Abnormalities – This include deletions, duplications, translocations and inversions. Overall, these occur in nearly 5% in infertile men. Apart from infertility, wives of these males are prone to abortions too.
Y Chromosome Microdeletions -This is an important microdeletion associated with male infertility. It involves abnormalities in the Y chromosome, and as this chromosome is present only in males, this problem affects the males exclusively. AZFc type of deletions are found more commonly in India. This type of genetic abnormality can be passed from father to son, making it particularly important to be ruled out prior to planning conception.
Testicular Disorder of Sex Development (DSD) – The DSD (46,XX male syndrome) is a rare disease. 46,XX males with testicular DSD have normal male genitalia, but develop abnormal sperm formation over time and even testicular shrinking.
CBAVD – The most common single-gene disorder is congenital bilateral aplasia of the vas deferens (CBAVD) i.e. the absence of the tube carrying sperms out of the testes. This leads to complete absence of sperms in the semen(azoospermia). Complete mutation this gene results in classical cystic fibrosis syndrome, including multiple other clinical symptoms and male infertility.
Multiple genes are involved in formation of hormones determining sequence of formation of the reproductive organs during the course development of a female body. Any defect in the interplay of these hormones leads to the abnormality in the development of the female organs like the uterus, fallopian tubes or the ovaries-a finding not so uncommon in the setting of female infertility. Premature ovarian failure(early menopause)is also quite routinely seen in this population.
Primary Ovarian Failure (POF)
Ovaries release the female hormones, responsible for the maintenance of female characters. Primary ovarian failure is the failure of the ovaries to function. So the woman presents with early menopause(stopping of monthly periods)and infertility. Several genes maybe associated with this disease.
47,XXX – Also known as trisomy X , is one of most common causes of premature ovarian failure.
Down syndrome – Down syndrome is usually associated with advanced age of the mother and is one the commonest genetic disorders. It is caused by the presence of an extra chromosome (three instead of two) in position 21. It is also referred to as trisomy 21.
Turner syndrome – Also known as monosomy X or 45,XO.These woman have abnormalities of the skeletal system(bones),heart,short height and non functional ovaries.The milder forms of his syndrome(mosaics)often present with infertility.
Fragile X syndrome – This a disorder characterized mainly by mental retardation and facial abnormalities. Infertility is common and at times runs in families so females having sisters or other family members suffering from infertility should get themselves tested at an infertility clinic at the earliest.
Galactosemia – This is a metabolic disorder related to improper utilisation of a sugar in the body. It has a strong genetic basis. Genetic counselling and medical intervention is very useful in families with this disease..
Polycystic Ovarian Syndrome(PCOS) – PCOS is a highly complex hormonal condition that affects 8-10% of women of the reproductive age group. PCOS is marked by excess of male hormones in the female and abnormality of sugar control, leading to multiple problems like irregular periods, weight gain, excessive hair growth, skin changes etc.
A large number of these women suffer from infertility as the egg release from the ovary(ovulation) is often defective. Early and persistent treatment with an infertility specialist leads to successful child bearing in a large majority of these patients. Multiple genes governing the sugar control and sex hormone regulation are involved.
Androgen Insensitivity Syndrome (AIS) – It is a very peculiar condition where when a person who is genetically male (who has one X and one Y chromosome) is resistant to male hormones and as a result, looks completely like a female externally.This “she” can never conceive. AIS is caused by genetic defects on the y chromosome.
Genetics of Infertility Common to Both Sexes:
Cystic fibrosis – Patients with CF suffer from systemic disorders in multiple organ disorders, including infertility. In males, there may often be the absence of the Vas(the tube transporting sperms from testis) and various semen abnormalities. This gene is expressed in various female reproductive organs like the cervix, oviduct, ovary, and uterus and it leads to menstrual irregularities and anovulation(lack of egg liberation from ovary).
Kallmann Syndrome (KS) – It is a genetic disorder that results from abnormal release of reproductive hormones from the brain. This leads to the absence of sexual maturity(puberty) or delayed appearance of beards and moustaches, even sexual issues. It also maybe associated with the absence of the sense of smell. Most of these men/women are infertile and need long term hormonal supplements.
Robertsonian Translocations – These are typical chromosomal abnormalities that may present with reproductive dysfunction, such as oligospermia (low sperm count) in males and miscarriages and infertility in females.
Infertility is a complex problem, identification of a single causative gene is usually not possible. But now there are multiple, more advanced tests in addition to the routinely done karyotyping, like fluorescence in situ hybridization(FISH) and comparative genomic hybridisation(CGH), available to identify chromosomal abnormalities.
Once the defect is identified, couples may benefit from the technology of pre-implantation genetic testing(PGT) in conjunction with in vitro fertilization (IVF). This, in simple words, involves, taking out the egg from female partner and sperm from male-forming the embryo in the laboratory and then testing all the embryos so made for the genetic abnormality suspected.
The abnormal, diseased embryos are discarded and only the “normal” embryos are then employed to attain pregnancy. This procedure gives the couple a unique opportunity to use advanced technology to select only the normal embryos and not leave anything to chance. The baby arising from this intervention almost ensures the freedom from the genetic disease in question.
Although a couple may otherwise have no fertility problems, but IVF and PGT together can still be given a serious thought to spare the affected couple from heartache in form of an abnormal baby in cases where there is a known genetic family history.
Even in some cases of recurrent abortion, this ploy may work-these couples may not have infertility, but all pregnancies end up in abortions. All blood tests turn out to be normal in these cases.
Many of these cases turn out to be of genetic origin on advanced testing. IVF with PGT can attempt to provide a live child to such a couple. Even in couples with late marriage at an older age, where the risk of chromosomally abnormal babies increases(especially if the woman is over 37-38 year old), this technology can be used to ensure the removal of all the defective embryos.
All the babies arising from these procedures are completely normal with no long term detrimental effects, either physically or mentally. This is an excellent option to eradicate a genetic disease running in families and ensure healthy subsequent off springs.
Jindal IVF clinic prides itself as being the only clinic in the region offering all these services under one roof, right from infertility treatment to in house genetic counselling, testing and feto maternal specialists. All advanced genetic testings, including PGT are being carried out in the clinic.