Genetic Factors Responsible for Recurrent Pregnancy Loss
Chromosomal abnormalities of the embryo account for at least 50% of first-trimester sporadic Miscarriages and 30% to 60% of further miscarriages in couples with recurrent miscarriage. More recently, analysis of miscarriage tissue by comparative genomic hybridization (a technique that detects chromosomal abnormalities without the need for culture) showed that conventional cytogenetic analysis underestimates the incidence of chromosomal anomalies and that the contribution of chromosomal abnormalities to first-trimester miscarriage is nearly 70%.
Parental Chromosomal Rearrangement (Translocation)
In approximately 3% to 5% of couples with recurrent miscarriage, one partner carries a balanced structural chromosomal abnormality. Women are more likely than men to carry most types of chromosomal rearrangements.The most common types of parental chromosomal abnormalities are balanced translocations. Although carriers of a balanced translocation are usually phenotypically normal, their pregnancies are at increased risk for miscarriage and may result in a live birth of a child with multiple congenital malformations or mental handicaps because of an unbalanced chromosomal arrangement. The risk of miscarriage is affected by the size and genetic content of the rearranged chromosomal segments.A less common chromosomal abnormality that may cause recurrent miscarriage is a chromosome inversion. This has been reported in 0.2% of couples with recurrent miscarriage.
Embryonic Aneuploidy and Polyploidy (Abnormal numbers of chromosomes)
Aneuploidy is caused by nondisjunction during meiosis that leads to the production of an extra chromosome (trisomy) or the deletion of a chromosome (monosomy). Triploidy occurs when there is a complete set of extra chromosomes. This usually arises from fertilization of the oocyte by two spermatozoa or from failure of one of the maturation divisions of either the oocyte or the spermatozoon. Tetraploidy (four times the haploid number) is usually caused by failure to complete the first zygotic division. In couples with recurrent miscarriage, conventional cytogenetic analysis reports the incidence of trisomy, polyploidy, and monosomy X in miscarriage tissue as 30%, 9%, and 4%, respectively. Most trisomies are the result of meiotic error as a result of advanced maternal age; however, gonadal mosaicism and sperm aneuploidies also increase the risk of trisomic conceptions. The risk of sex chromosome monosomy and polyploidy conceptions do not increase with maternal age.
Molecular Mechanisms - The latest thoughts:
Recent advances in molecular genetic technology highlighted the importance of certain mechanisms,such as single-gene mutations and skewed X chromosome inactivation,in the etiology of pregnancy loss.
Showing posts with label Genetic diseases. Show all posts
Showing posts with label Genetic diseases. Show all posts
Monday, March 9, 2009
Saturday, March 7, 2009
Why genetic counseling is sometimes important before and during pregnancy
The main reasons why a woman seeks genetic counseling prior to or during her pregnancy mainly fall in the following groups:
Ethnic predispositions to inherited disorders
Family history of a baby with genetic disorders.
History of babies born with birth defects
Advanced maternal age.
Abnormal test results in pregnancy.
Exposure to potentially harmful substances or, organisms during pregnancy.
Let us consider each aspect one by one
Significance of Ethnic origin of parents
Ethnic predilection to a genetic disorder is definite necessity to undergo genetic testing and counseling during pregnancy, and even better if before. The following diseases are a autosomal recessive. They need two genes—one from each otherwise healthy parent—for the condition to manifest in a child.
The following diseases are few of the conditions transmitted in this way:
Sickle Cell disease.
In sickle cell disease, the usually supple and round red blood cells become stiff and crescent-shaped. This condition causes anemia, bouts of pain caused by obstructed blood vessels, and enhanced vulnerability to serious infections like pneumonia. About 1 out of 10 African-Americans carries one recessive gene for sickle cell disease. This condition is called sickle cell trait. More than 50,000 Americans have both the copies of the gene in them and have sickle cell disease. When both parents have sickle cell trait, they have a one in four probability with each pregnancy of having a child with the sickle cell disease. This can be diagnosed during pregnancy by prenatal screening or, at birth by carrying on investigation on the new born.
Thalassemia.
Those of Asian and Mediterranean origin including Greeks and Italians are at threat of inheriting thalassemia when both partners carry a single recessive gene also known as thalassemia trait. Some forms of thalassemia like Majors are very grave and may end in stillbirth or cause severe anemia, needing a continuous blood transfusions for the child or sometimes bone marrow transplantation may be required. Prenatal screening is possible for thalassemia.
Tay-Sachs disease.
Those from Eastern European (Ashkenazi) Jewish descent might be carriers of the recessive genes for a number of disorders, of which Tay-Sachs disease is very important. Babies with Tay-Sachs disease are deficient in an enzyme, hexosaminidase A from birth. This is essential for nerve cell to function properly. These children steadily deteriorate their mental and physical function and usually expire before they reach their fifth birthday. Approximately 1 out of 25 Ashkenazi Jews is a Tay-Sachs carrier. The ratio for Sephardic Jews (those originally from Spain, Portugal, and North Africa) is about 1 out of 100. Screening with a simple blood test during or before pregnancy is a routine practice, and prenatal testing is possible.
Gaucher disease
Another recessive genetic disease characterized by an enzyme deficiency is Gaucher disease. It is commoner than Tay-Sachs disease, with a gene carrier ratio of approximately 1 out of 12 Ashkenazi Jews.
In Gaucher disease there is building up of fatty deposits in the liver and spleen. This results in the enlargement of these organs. It can range from mild to severe. Carrier screening and prenatal diagnosis are possible to those with a family history of the condition.
Cystic fibrosis.
Caucasians are at a bigger risk for cystic fibrosis (CF), in general a severe disease condition characterized by thick and sticky mucus secretions mainly in the lungs and other parts of the body. There are roughly 30,000 Americans with Cystic Fibrosis and as many as 1 Caucasian American out of 20 may carry one of the many types of the gene for Cystic Fibrosis.
Cystic Fibrosis is infrequent in Latinos, African-Americans, and very unusual among the Asians. When both the partners of a couple carry such a gene, they have a one in four probability with each pregnancy of giving birth to a child with Cystic Fibrosis.
Currently, a DNA-based investigation for the cystic fibrosis gene is existing, particularly to couple with a family history of Cystic Fibrosis. In the majority of instances, a fetus at risk for Cystic Fibrosis with a family history can be recognized through prenatal screening.
The diseases mentioned above are only the tip of the icebarg of the numerous genetic disorders for which specific ethnic groups are particularly at risk.
Ethnic predispositions to inherited disorders
Family history of a baby with genetic disorders.
History of babies born with birth defects
Advanced maternal age.
Abnormal test results in pregnancy.
Exposure to potentially harmful substances or, organisms during pregnancy.
Let us consider each aspect one by one
Significance of Ethnic origin of parents
Ethnic predilection to a genetic disorder is definite necessity to undergo genetic testing and counseling during pregnancy, and even better if before. The following diseases are a autosomal recessive. They need two genes—one from each otherwise healthy parent—for the condition to manifest in a child.
The following diseases are few of the conditions transmitted in this way:
Sickle Cell disease.
In sickle cell disease, the usually supple and round red blood cells become stiff and crescent-shaped. This condition causes anemia, bouts of pain caused by obstructed blood vessels, and enhanced vulnerability to serious infections like pneumonia. About 1 out of 10 African-Americans carries one recessive gene for sickle cell disease. This condition is called sickle cell trait. More than 50,000 Americans have both the copies of the gene in them and have sickle cell disease. When both parents have sickle cell trait, they have a one in four probability with each pregnancy of having a child with the sickle cell disease. This can be diagnosed during pregnancy by prenatal screening or, at birth by carrying on investigation on the new born.
Thalassemia.
Those of Asian and Mediterranean origin including Greeks and Italians are at threat of inheriting thalassemia when both partners carry a single recessive gene also known as thalassemia trait. Some forms of thalassemia like Majors are very grave and may end in stillbirth or cause severe anemia, needing a continuous blood transfusions for the child or sometimes bone marrow transplantation may be required. Prenatal screening is possible for thalassemia.
Tay-Sachs disease.
Those from Eastern European (Ashkenazi) Jewish descent might be carriers of the recessive genes for a number of disorders, of which Tay-Sachs disease is very important. Babies with Tay-Sachs disease are deficient in an enzyme, hexosaminidase A from birth. This is essential for nerve cell to function properly. These children steadily deteriorate their mental and physical function and usually expire before they reach their fifth birthday. Approximately 1 out of 25 Ashkenazi Jews is a Tay-Sachs carrier. The ratio for Sephardic Jews (those originally from Spain, Portugal, and North Africa) is about 1 out of 100. Screening with a simple blood test during or before pregnancy is a routine practice, and prenatal testing is possible.
Gaucher disease
Another recessive genetic disease characterized by an enzyme deficiency is Gaucher disease. It is commoner than Tay-Sachs disease, with a gene carrier ratio of approximately 1 out of 12 Ashkenazi Jews.
In Gaucher disease there is building up of fatty deposits in the liver and spleen. This results in the enlargement of these organs. It can range from mild to severe. Carrier screening and prenatal diagnosis are possible to those with a family history of the condition.
Cystic fibrosis.
Caucasians are at a bigger risk for cystic fibrosis (CF), in general a severe disease condition characterized by thick and sticky mucus secretions mainly in the lungs and other parts of the body. There are roughly 30,000 Americans with Cystic Fibrosis and as many as 1 Caucasian American out of 20 may carry one of the many types of the gene for Cystic Fibrosis.
Cystic Fibrosis is infrequent in Latinos, African-Americans, and very unusual among the Asians. When both the partners of a couple carry such a gene, they have a one in four probability with each pregnancy of giving birth to a child with Cystic Fibrosis.
Currently, a DNA-based investigation for the cystic fibrosis gene is existing, particularly to couple with a family history of Cystic Fibrosis. In the majority of instances, a fetus at risk for Cystic Fibrosis with a family history can be recognized through prenatal screening.
The diseases mentioned above are only the tip of the icebarg of the numerous genetic disorders for which specific ethnic groups are particularly at risk.
Why and what is Genetic Counseling?
Genetic counseling is useful to any woman, either before or during pregnancy, who is worried about the danger to her unborn baby posed by a number of situations.
Likewise, families probing for answers of the manifestation of a genetic condition or birth defect in a family member can look for genetic counseling and testing to calculate the probability that other family members will be affected. Far more than just testing, the genetic counseling process offers education about human inheritance and information about spe¬cific disorders of apprehension to a family.
Moreover, prenatal tests of fetal health before birth can now forecast earlier and with even greater accurateness whether there is a probability of an inherited disorder or birth defect.
Nevertheless, it is not always easy to make a decision about when to use this expertise, how to infer the results, and what course of action to take. Families dealing with the likelihood of an inherited disorder or birth defect in an unborn baby, or confronting the reality of a child or adult who is already affected, need the help of skilled individuals, medical geneti¬cists and genetic counselors to ascertain a diagnosis and educate about the disorder, explaining the potential risks to other family members, choosing a course of action, and coming to terms with their deci¬sion. This process is called genetic counseling.
- A family history of genetic disease or birth defects
- A chromosome problem associated with advanced maternal age such as Down syndrome
- Exposure to potentially harmful sub¬stances,
- Two or more unexplained miscarriages or a previous baby with a birth defect.
Likewise, families probing for answers of the manifestation of a genetic condition or birth defect in a family member can look for genetic counseling and testing to calculate the probability that other family members will be affected. Far more than just testing, the genetic counseling process offers education about human inheritance and information about spe¬cific disorders of apprehension to a family.
Moreover, prenatal tests of fetal health before birth can now forecast earlier and with even greater accurateness whether there is a probability of an inherited disorder or birth defect.
Nevertheless, it is not always easy to make a decision about when to use this expertise, how to infer the results, and what course of action to take. Families dealing with the likelihood of an inherited disorder or birth defect in an unborn baby, or confronting the reality of a child or adult who is already affected, need the help of skilled individuals, medical geneti¬cists and genetic counselors to ascertain a diagnosis and educate about the disorder, explaining the potential risks to other family members, choosing a course of action, and coming to terms with their deci¬sion. This process is called genetic counseling.
Problems of Marriages between blood relations - Consanguineous Marraige
Consanguineous marriages, or marriages between blood relatives, are fairly common within certain cul¬tures. Unfortunately, children from these types of marriages may be at a very elevated risk for genetic illness. For a child to inherit a recessive disease, both parents must be carriers.
For a rare recessive disorder, where the chance of any individual being a carrier is one in 1000, the odds of both parents being carriers would be 1 in 1,000,000 (1/1000 x 1/1000). The chance that any given fetus will inherit defective genes from both parents is 1 in 4,000,000. (1/4 x 1/1000).
Let's instead consider two parents that are first cousins. The most likely way that they would both be carriers would be if one of their grandparents was a carrier, and had passed the disease gene to both of their parents. Since there are two great-grand¬parents at the top of the consanguinity loop, the chance that one would be a carrier would be 2/1000 (2 x 1/1000), There is a 1/2 chance that any given child will inherit the defective gene, so the odds that both the grandparents would be carriers would be 1/4 (1/2 x 1/2), assuming that one great-grandparent was a carrier (remember there is a 2/1000 chance of that) The odds that both parents would be carriers, again assuming that their parents were carriers, is again 1/4 (1/2 x 1/2).
Finally, the chance that any child of theirs would be affected is 1/4, assuming they are both carriers. When we multiply out the proba¬bilities of each of these people being carriers and a child being affected, we get 1/32,000 (2/1,000 x 1/4 x 1/4 x 1/4). While this is quite a low number, com¬pared to the risk for a child from a non-consanguineous marriage (1/4,000,000), the risk to the child from the consanguineous marriage is increased by 125-fold.
For a rare recessive disorder, where the chance of any individual being a carrier is one in 1000, the odds of both parents being carriers would be 1 in 1,000,000 (1/1000 x 1/1000). The chance that any given fetus will inherit defective genes from both parents is 1 in 4,000,000. (1/4 x 1/1000).
Let's instead consider two parents that are first cousins. The most likely way that they would both be carriers would be if one of their grandparents was a carrier, and had passed the disease gene to both of their parents. Since there are two great-grand¬parents at the top of the consanguinity loop, the chance that one would be a carrier would be 2/1000 (2 x 1/1000), There is a 1/2 chance that any given child will inherit the defective gene, so the odds that both the grandparents would be carriers would be 1/4 (1/2 x 1/2), assuming that one great-grandparent was a carrier (remember there is a 2/1000 chance of that) The odds that both parents would be carriers, again assuming that their parents were carriers, is again 1/4 (1/2 x 1/2).
Finally, the chance that any child of theirs would be affected is 1/4, assuming they are both carriers. When we multiply out the proba¬bilities of each of these people being carriers and a child being affected, we get 1/32,000 (2/1,000 x 1/4 x 1/4 x 1/4). While this is quite a low number, com¬pared to the risk for a child from a non-consanguineous marriage (1/4,000,000), the risk to the child from the consanguineous marriage is increased by 125-fold.
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