The failure to conceive even after a year of unprotected sexual intercours is defined as infertility. Of the total human population about 15 percent are infertile (1).
In the present era of high tech facilities, life has become very fast. Priorities have taken a shift. Family life has been sacrificed over better career prospects. Delayed marriages followed by delayed child birth has had some profound impact on not only maternal health but also on the offsprings. Age related maternal and paternal chromosomal abberations have become quite common in the gametes of present population which have increased the infertility rate among the people of reproductive age. In this case study we have come across a couple who has been practising contraception for many years and later wish to start a family when the female partner advances to 36 years of age. They are aware of age related pregnancy complications and so are wise enough to consult geneticist to avoid any such complications and give birth to healthy child.
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The failure of the couple to conceive reflects their infertility status. Since, infertility is not only the female issue, therefore in the present report, I've discussed the likelihood of both female and male infertility and briefly summarized how the use of assisted reproductive technologies can benefit this couple.
This case study is about a couple wishing to start a family but are not successful. Since the lady is already 38 years of age, so there are more chances of age related genetic abnormalities being developed in her gametes as age plays almost negligible role in male infertility.
The couple worry that advancing age of the female partner might affect her child bearing ability and increase the likelihood of mis-carriage if she is able to conceive naturally. They also want to make sure that they give birth to a healthy child, free from any genetic and metabolic abnormalities if they happen to be present in their family gene pool. Both of them are carrying Î”F508 deletion in their CFTR gene which implies one in four of their progeny will be developing the Cystic Fibrosis disease.
Two years post genetic counselling, the female partner is still not able to conceive naturally. As her FSH level is relatively higher than the normal level during early phase of the cycle, therefore this points out that her age is affecting her ability to conceive.
Possible gene mutations in the couple:
Since the couple are interested in knowing their genetic status and its likely effect on the future offspring, therefore following are some of the main gene mutations that are quite common over the other. However it must be taken into account that certain gene mutations are more common in certain groups of population and over certain geographic locations as well.Triplet repeat single gene mutations, such as- fragile X. MD, freidrich ataxia, huntington disease, SCA, SBMA are some of the common gene mutations.
* Fragile-X is characterised by repeat of CGG trinucleotide to such an extent that it hinders the transcription of FMR1 gene and the consequences are mental retardation. This syndrome is more prevelant in males but females dveloping full mutaion are likely to have mosaic Turner's syndrome (2)
* Another common chromosomal variation is Centric fusion translocations of the t(DqDq) type (3). In centric fusion translocation, also refered to as Robertsonian translocations, the acrocentric chromosomes fuse together (long arms). Chromosome 13-15, 21 and 22 are acrocentric. Trisomy 13 (Patau) and trisomy 22 (down) also result from these translocations.
* Cystic fibrosis: It is a genetic disorder in which the mucous and the sweat glands of the body clog up. It is an autosomal linked recessive disease in which mutations occur on the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Many mutations are responsible for this diseased state which have different frequency of occurance in different populations of the world. In our case study, both the partners have been detected to carry a Î”F508 mutation in the CFTR gene. Phenylalaline is present at the 508 position of N-terminal binding protein (NBD1) and its deletion causes misfolding of NBD1 which leads to non-functional CFTR protein in the apical membrane of epithelial cells leading to cystic fibrosis (4). In Europeon population, between 1 in 20 and 1 in 25 individuals are carriers of this mutation while the children of these affected individuals are between 1 in 40 and 1 in 50 (5). The cystic fibrosis child fails to thrive and thus prenatal diagnosis of this disease is required to prevent its occurance.
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Likelihood of female infertility:
There are various factors of female inferility. Some of the possible genetic causes have been discussed here.
Endometriosis is a leading cause of infertility among women. chronic pelvic pain, dysmenorrhoea, menorrhagia and dyspareunia mark the onset of this disease. Finding has been obtained regarding the association of polychlorinated biphenyls (PCBs) and GSTM1 null mutation in pathogenesis of endometriosis (6). Non-random chromosomal abnormalities also lead to the occurance of Leiomyomas. Leiomyomas is defined as benign uterine tumors and their origin is myometrial cells. It has been now known that altered miRNA expression leads to leiomyomas. The miRNA that have been identified are let-7 family, miR-21, miR-23b, miR-29b, miR-197, miR-34a, miR-125b, and miR-26a (7). However this disease is more prevelant in African women, therefore its less likely that the female in this case study might suffer from it. Despite the ethnic origin, the miRNA expression can be monitored for this female to determine presence of any tumoric growth. Not only this, miRNA also aid in intraovarian regulation thats necessary for ovarian cellular activities (8), hence analysis of miRNA expression will reveal the health of the ovaries as well.
Genetic tests that can be conducted on the female partner to determine her genetis status:
The traditional approach of linkage analysis and gene mapping be used to study the occurance of most common mutations. Microarray technology can be employed to study the expression of above mentioned genes and also detect SNPs.Blood test will reveal her hormonal level for follicle stimulating hormone, leutinizing hormone, estrogen, progesterone, etc. These levels will help to dertermine her mentrual cycle abnormalities and the likely consequence on the success of in vitro techniques of reproduction. For example to boost the ovulation, super ovulation technique can be employed afta determining the hormonal levels.
Genetics of Age and Infertility:
The breaks in double stranded DNA and the failure of the DNA repair mechanism is proportional to age. The DNA repair enzymes also under go mutations so as to further raise the damage n hence mutations n abberations are more prevelant with increase in age. In the older female gametes, the differential expression of transcripts increases and pattern of mRNA degradation undergoes a change (altered miRNA expression can be attributed to this). Not only this but the spindle assembly checkpoints become vunerable as microtubule-kinetochore interactions become highly prone to errors (9). These molecular level changes increases the production of aneuploid gametes via the mechanism of non-disjunction of homologous chromosomes.
Suggestions for the female partner:
After introspection into the age realted infertility issues, it seems obvious that the couple has to opt for assisted reproductive technology. Since the female is 38 years of age and her FSH level in early phase of menstrual cycle reflect the fact that she is heading towards her menopause, therefore we need to look for ways so as to boost the production of oocytes. One way to culture oocytes in vitro is through culturing the ovarian cortex. For non-rodent mammals, primordial follicles are not self sustaining in the in vitro enviornment while preantral follicles do grow independently. Hence culturing them to the antral stage will induce steroidogenic funtions and cyto-nucleoplasmic maturations in the gametes to give rise to fertile metaphase II oocytes ready for fertilization (10).
Another novel approach in the production of oocytes is use of stem cell technology. Since every female is born with a limited number of oocytes, therefore culturing stem cells to produce newer stock of oocytes will not only erradicate the occurance of chromosomal abnormalities arising due to age but also can be monitered for any other genetic variations (11).
Likelihood of male infertility:
In males, the infertility issue revolves around the production, motility and morphology of the sperms. Likewise there are three abnormalities associated with sperms viz: oligozoospermia, asthenozoospermia and teratozoospermia. The main causes of male infertility can be summarised below:
* The micro-deletions on the Y-chromosome are the major factors contributing to infertility in males. One of the main deletion is that of Azoospermia factor (AZF) which present in Yq11 locus. This deletion has adverse effect on DAZ (deleted in Azoospermia) gene which acts as a candidate gene. The genes that lie near the break points are termed as candidate genes. Another microdeletion called gr/gr deletion has been noticed in azoospermic patients (1).
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* Since mitochondria is the powerhouse of every cell, likewise sperm cell derives its energy for development and movement from the mitochondria. Hence any mutations in the mitochondrial DNA will lead to poor sperm production. The DNA polymerase (gamma) which repairs the mtDNA occurs on chromosome 15 (15q25). Its mutation disrupts ATP synthesis. Also reactive oxygen species are produced in the mitochondria. There over production causes oxidative stress in the cell which also deteriorates the DNA and hence leads to infertility (1).
* Recent discoveries have shown the role of miRNA in determining fertility status in males as well. miRNA are short RNA sequences that donot transcribe, rather they base pair with target mRNA and aid inthe post transcriptional gene silencing. So they repress translation in meiotic synapsis stage (12).
* Low levels of Septin12 protein leads to sperm maturation arrest and results in sperms with abnormal morphology. Septin is a GTP binding protein and finds many roles in cellular compartmentalisation, cellular trafficking, etc (13).
* Single nucleotide polymorphism(SNP) in PRDM9 gene has also been reported to cause azoospermia (14).
Genetics of aneuploidy in males:
The meiotic errors occuring at the haploid germ cell stage accounts for aneuploidy in sperm cells. Alterations in synaptonemal complex proteins (SCP1 and SCP3) affect the chromosome synapses and likewise alterations in Human mutL homologue 1(MLH1) reduces the crossing over and subsequent meiotic recombination. These result in production of aneuploid gametes (12).
Tests that can be conducted on the male partner to determine his genetic status:
Semen analysis,screening for Yq microdeletions, antioxidant therapy to prevent the oxidative stress, chromosome banding technique (15), MASA technology (16). Karyotyping must be carried out to determine the klinefelter status of the male partner since this syndrome reflects infertility in males.
Overcoming the infertility barrier for the couple (use of assisted reproductive technologies):
The couple can be advised to undergo in virto fertilization (IVF) technique. The success of the pregnancy can be tracked by determining the levels of Claudin4 (CLDN4) and leukameia inhibitory factor (LIF). CLDN4 protein help in embryo implantation while LIF is associated with endometrial tissue. For successful implantation post IVF, weak CLDN4 and strong LIF expression has been observed to work best (17).
Various genetic factors have been brought forward in this case study which reveal the infertility status of both males and females. Age plays a significant amount of role in causing infertility in otherwise normal females as we have observed that probability of aneuploidy and other chromosomal variations and mutations increase with increase in maternal age. We have observed the role of miRNA in both oocyte and sperm maturation and hence techniques that employ the detection of miRNA expression will prove useful to diagnose the fertility level in both the partners.
Finally, various ART are avaialble and have higher success rate than before as more and more complicated cases have achieved success in ataining pregnancy. So, accurate genetic tests, combined with hormonal therapy prior to the use of ART will help to successfully establish pregnancy.
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