Human genetic disease - Prevention, Diagnosis, Treatment
The management of genetic disease can be divided into counseling, diagnosis, and treatment. In brief, the fundamental purpose of genetic counseling is to help the individual or family understand their risks and options and to empower them to make informed decisions. Diagnosis of genetic disease is sometimes clinical, based on the presence of a given set of symptoms, and sometimes molecular, based on the presence of a recognized gene mutation, whether clinical symptoms are present or not. The cooperation of family members may be required to achieve diagnosis for a given individual, and, once accurate diagnosis of that individual has been determined, there may be implications for the diagnoses of other family members. Balancing privacy issues within a family with the ethical need to inform individuals who are at risk for a particular genetic disease can become extremely complex.
Although effective treatments exist for some genetic diseases, for others there are none. It is perhaps this latter set of disorders that raises the most troubling questions with regard to presymptomatic testing, because phenotypically healthy individuals can be put in the position of hearing that they are going to become ill and potentially die and that there is nothing they or anyone else can do to stop it. Fortunately, with time and research, this set of disorders is slowly becoming smaller.
Genetic counseling
Genetic counseling represents the most direct medical application of the advances in understanding of basic genetic mechanisms. Its chief purpose is to help people make responsible and informed decisions concerning their own health or that of their children. Genetic counseling, at least in democratic societies, is nondirective; the counselor provides information, but decisions are left up to the individual or the family.
In the case of single-gene Mendelian inheritance, the disease may be passed on as an autosomal recessive, autosomal dominant, or sex-linked recessive trait, as discussed in the section Classes of genetic diseases. If the prospective parents already have a child with an autosomal recessive inherited disease, they both are considered by definition to be carriers, and there is a 25 percent risk that each future child will be affected. If one of the parents carries a mutation known to cause an autosomal dominant inherited disease, whether that parent is clinically affected or not, there is a 50 percent risk that each future child will inherit the mutation and therefore may be affected. If, however, the couple has borne a child with an autosomal dominant inherited disease though neither parent carries the mutation, then it will be presumed that a spontaneous mutation has occurred and that there is not a markedly increased risk for recurrence of the disease in future children. There is a caveat to this reasoning, however, because there is also the possibility that the new mutation might have occurred in a progenitor germ cell in one of the parents, so that some unknown proportion of that individual’s eggs or sperm may carry the mutation, even though it is absent from the somatic cells—including blood, which is generally the tissue sampled for testing. This scenario is called germline mosaicism. Finally, with regard to X-linked disorders, if the pedigree or carrier testing suggests that the mother carries a gene for a sex-linked disease, there is a 50 percent chance that each son will be affected and that each daughter will be a carrier.
Counseling for chromosomal inheritance most frequently involves either an inquiring couple (consultands) who have had a child with a known chromosomal disorder, such as Down syndrome, or a couple who have experienced multiple miscarriages. To provide the most accurate recurrence risk values to such couples, both parents should be karyotyped to determine if one may be a balanced translocation carrier. Balanced translocations refer to genomic rearrangements in which there is an abnormal covalent arrangement of chromosome segments, although there is no net gain or loss of key genetic material. If both parents exhibit completely normal karyotypes, the recurrence risks cited are low and are strictly empirical.
Most of the common hereditary birth defects, however, are multifactorial. (See the section Diseases caused by mutifactorial inheritance.) If the consulting couple have had one affected child, the empirical risk for each future child will be about 3 percent. If they have borne two affected children, the chance of recurrence will rise to about 10 percent. Clearly these are population estimates, so that the risks within individual families may vary.
In this example, the consultand wishes to know her risk of having a child with DMD. The family’s pedigree is illustrated in the figure. It is known that the consultand’s grandmother (I-2) is a carrier, since she had two affected sons (spontaneous mutations occurring in both brothers would be extremely unlikely). What is uncertain is whether the consultand’s mother (II-4) is also a carrier. The Bayesian method for calculating the consultand’s risk is as follows:
If II-4 is a carrier (risk = 1/5), then there is a 1/2 chance that the consultand is also a carrier, so her total empirical risk is 1/5 × 1/2 = 1/10. If she becomes pregnant, there is a 1/2 chance that her child will be male and a 1/2 chance that the child, regardless of sex, will inherit the familial mutation. Hence, the total empirical risk for the consultand (III-2) to have an affected child is 1/10 1/2 1/2 = 1/40. Of course, if the familial mutation is known, presumably from molecular testing of an affected family member, the carrier status of III-2 could be determined directly by molecular analysis, rather than estimated by Bayesian calculation. If the family is cooperative and an affected member is available for study, this is clearly the most informative route to follow, because the risk for the consultand to carry the familial mutation would be either 1 or 0, and not 1/10. If her risk is 1, then each of her sons will have a 1/2 chance of being affected. If her risk is 0, none of her children will be affected (unless a new mutation occurs, which is very rare).
Current forms of prenatal diagnosis can be divided into two classes, those that are apparently noninvasive and those that are more invasive. At present the noninvasive tests are generally offered to all pregnant women, while the more-invasive tests are generally recommended only if some risk factors exist. The noninvasive tests include ultrasound imaging and maternal serum tests. Serum tests include one for alphafetoprotein (AFP) or one for alphafetoprotein, estriol, and human chorionic gonadotropin (triple screen). These tests serve as screens for structural fetal malformations and for neural tube closure defects. The triple screen also can detect some cases of Down syndrome, although there is a significant false-positive and false-negative rate.
More-invasive tests include amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, and, upon rare occasion, preimplantation testing of either a polar body or a dissected embryonic cell. Amniocentesis is a procedure in which a long, thin needle is inserted through the abdomen and uterus into the amniotic sac, enabling the removal of a small amount of the amniotic fluid bathing the fetus. This procedure is generally performed under ultrasound guidance between the 15th and 17th weeks of pregnancy, and, although it is generally regarded as safe, complications can occur, ranging from cramping to infection or loss of the fetus. The amniotic fluid obtained can be used in each of three ways: (1) living fetal cells recovered from this fluid can be induced to grow and can be analyzed to assess chromosome number, composition, or structure; (2) cells recovered from the fluid can be used for molecular studies; and (3) the amniotic fluid itself can be analyzed biochemically to determine the relative abundance of a variety of compounds associated with normal or abnormal fetal metabolism and development. Amniocentesis is typically offered to pregnant women over age 35, because of the significantly increased rate of chromosome disorders observed in the children of older mothers. A clear advantage of amniocentesis is the wealth of material obtained and the relative safety of the procedure. The disadvantage is timing: results may not be received until the pregnancy is already into the 19th week or beyond, at which point the possibility of termination may be much more physically and emotionally wrenching than if considered earlier.
Genetic testing procedures can be divided into two different groups: (1) testing of individuals considered at risk from phenotype or family history and (2) screening of entire populations, regardless of phenotype or personal family history, for evidence of genetic disorders common in that population. Both forms are currently pursued in many societies. Indeed, with the explosion of information about the human genome and the increasing identification of potential “risk genes” for common disorders, such as cancer, heart disease, or diabetes, the role of predictive genetic screening in general medical practice is likely to increase.
At present, adults are generally tested for evidence of genetic disease only if personal or family history suggests they are at increased risk for a given disorder. A typical example would be a young man whose father, paternal aunt, and older brother have all been diagnosed with early onset colorectal cancer. Although this person may appear perfectly healthy, he is at significantly increased risk to carry mutations associated with familial colorectal cancer, and accurate genetic testing could enable heightened surveillance (e.g., frequent colonoscopies) that might ultimately save his life.
Carrier testing for adults in most developed nations is generally offered only if family history or ethnic origins suggest an increased risk of having a particular disease. A typical example would be to offer carrier testing for cystic fibrosis to a couple including one member who has a sibling with the disorder. Another would be to offer carrier testing for Tay-Sachs disease to couples of Ashkenazic Jewish origin, a population known to carry an increased frequency of Tay-Sachs mutations. The same would be true for couples of African or Mediterranean descent with regard to sickle cell anemia or thalassemia, respectively. Typically, in each of these cases a genetic counselor would be involved to help the individuals or couples understand their options and make informed decisions.
genetic screening, gene therapy, genome editing, carrier testing, personalized medicine, prenatal diagnosis, genetic counseling, CRISPR technology, pharmacogenomics, biomarkers, epigenetics, molecular diagnostics, genetic risk factors, family history, gene mutation, next-generation sequencing, rare diseases, therapeutic cloning, stem cell therapy, bioinformatics
Although effective treatments exist for some genetic diseases, for others there are none. It is perhaps this latter set of disorders that raises the most troubling questions with regard to presymptomatic testing, because phenotypically healthy individuals can be put in the position of hearing that they are going to become ill and potentially die and that there is nothing they or anyone else can do to stop it. Fortunately, with time and research, this set of disorders is slowly becoming smaller.
Genetic counseling
Genetic counseling represents the most direct medical application of the advances in understanding of basic genetic mechanisms. Its chief purpose is to help people make responsible and informed decisions concerning their own health or that of their children. Genetic counseling, at least in democratic societies, is nondirective; the counselor provides information, but decisions are left up to the individual or the family.
Calculating risks of known carriers
Most couples who present themselves for preconceptional counseling fall into one of two categories: those who have already had a child with genetically based problems, and those who have one or more relatives with a disease they think might be inherited. The counselor must confirm the diagnosis in the affected person with meticulous accuracy, so as to rule out the possibility of alternative explanations for the clinical symptoms observed. A careful family history permits construction of a pedigree that may illuminate the nature of the inheritance (if any), may affect the calculation of risk figures, and may bring to light other genetic influences. The counselor, a certified health-care professional with special training in medical genetics, must then decide whether the disease in question has a strong genetic component and, if so, whether the heredity is single-gene, chromosomal, or multifactorial.In the case of single-gene Mendelian inheritance, the disease may be passed on as an autosomal recessive, autosomal dominant, or sex-linked recessive trait, as discussed in the section Classes of genetic diseases. If the prospective parents already have a child with an autosomal recessive inherited disease, they both are considered by definition to be carriers, and there is a 25 percent risk that each future child will be affected. If one of the parents carries a mutation known to cause an autosomal dominant inherited disease, whether that parent is clinically affected or not, there is a 50 percent risk that each future child will inherit the mutation and therefore may be affected. If, however, the couple has borne a child with an autosomal dominant inherited disease though neither parent carries the mutation, then it will be presumed that a spontaneous mutation has occurred and that there is not a markedly increased risk for recurrence of the disease in future children. There is a caveat to this reasoning, however, because there is also the possibility that the new mutation might have occurred in a progenitor germ cell in one of the parents, so that some unknown proportion of that individual’s eggs or sperm may carry the mutation, even though it is absent from the somatic cells—including blood, which is generally the tissue sampled for testing. This scenario is called germline mosaicism. Finally, with regard to X-linked disorders, if the pedigree or carrier testing suggests that the mother carries a gene for a sex-linked disease, there is a 50 percent chance that each son will be affected and that each daughter will be a carrier.
Counseling for chromosomal inheritance most frequently involves either an inquiring couple (consultands) who have had a child with a known chromosomal disorder, such as Down syndrome, or a couple who have experienced multiple miscarriages. To provide the most accurate recurrence risk values to such couples, both parents should be karyotyped to determine if one may be a balanced translocation carrier. Balanced translocations refer to genomic rearrangements in which there is an abnormal covalent arrangement of chromosome segments, although there is no net gain or loss of key genetic material. If both parents exhibit completely normal karyotypes, the recurrence risks cited are low and are strictly empirical.
Most of the common hereditary birth defects, however, are multifactorial. (See the section Diseases caused by mutifactorial inheritance.) If the consulting couple have had one affected child, the empirical risk for each future child will be about 3 percent. If they have borne two affected children, the chance of recurrence will rise to about 10 percent. Clearly these are population estimates, so that the risks within individual families may vary.
Estimating probability: Bayes’s theorem
As described above, the calculation of risks is relatively straightforward when the consultands are known carriers of diseases due to single genes of major effect that show regular Mendelian inheritance. For a variety of reasons, however, the parental genotypes frequently are not clear and must be approximated from the available family data. Bayes’s theorem, a statistical method first devised by the English clergyman-scientist Thomas Bayes in 1763, can be used to assess the relative probability of two or more alternative possibilities (e.g., whether a consultand is or is not a carrier). The likelihood derived from the appropriate Mendelian law (prior probability) is combined with any additional information that has been obtained from the consultand’s family history or from any tests performed (conditional probability). A joint probability is then determined for each alternative outcome by multiplying the prior probability by all conditional probabilities. By dividing the joint probability of each alternative by the sum of all joint probabilities, the posterior probability is arrived at. Posterior probability is the likelihood that the individual, whose genotype is uncertain, either carries the mutant gene or does not. One example application of this method, applied to the sex-linked recessive disease Duchenne muscular dystrophy (DMD), is given below.In this example, the consultand wishes to know her risk of having a child with DMD. The family’s pedigree is illustrated in the figure. It is known that the consultand’s grandmother (I-2) is a carrier, since she had two affected sons (spontaneous mutations occurring in both brothers would be extremely unlikely). What is uncertain is whether the consultand’s mother (II-4) is also a carrier. The Bayesian method for calculating the consultand’s risk is as follows:
If II-4 is a carrier (risk = 1/5), then there is a 1/2 chance that the consultand is also a carrier, so her total empirical risk is 1/5 × 1/2 = 1/10. If she becomes pregnant, there is a 1/2 chance that her child will be male and a 1/2 chance that the child, regardless of sex, will inherit the familial mutation. Hence, the total empirical risk for the consultand (III-2) to have an affected child is 1/10 1/2 1/2 = 1/40. Of course, if the familial mutation is known, presumably from molecular testing of an affected family member, the carrier status of III-2 could be determined directly by molecular analysis, rather than estimated by Bayesian calculation. If the family is cooperative and an affected member is available for study, this is clearly the most informative route to follow, because the risk for the consultand to carry the familial mutation would be either 1 or 0, and not 1/10. If her risk is 1, then each of her sons will have a 1/2 chance of being affected. If her risk is 0, none of her children will be affected (unless a new mutation occurs, which is very rare).
Diagnosis
Prenatal diagnosis
Perhaps one of the most sensitive areas of medical genetics is prenatal diagnosis, the genetic testing of an unborn fetus, because of fears of eugenic misuse or because some couples may choose to terminate a pregnancy depending on the outcome of the test. Nonetheless, prenatal testing in one form or another is now almost ubiquitous in most industrialized nations, and recent advances both in testing technologies and in the set of “risk factor” genes to be screened promise to make prenatal diagnosis even more widespread. Indeed, parents may soon be able to ascertain information not only about the sex and health status of their unborn child but also about his or her complexion, personality, and intellect. Whether parents should have access to all of this information and how they may choose to use it are matters of much debate.Current forms of prenatal diagnosis can be divided into two classes, those that are apparently noninvasive and those that are more invasive. At present the noninvasive tests are generally offered to all pregnant women, while the more-invasive tests are generally recommended only if some risk factors exist. The noninvasive tests include ultrasound imaging and maternal serum tests. Serum tests include one for alphafetoprotein (AFP) or one for alphafetoprotein, estriol, and human chorionic gonadotropin (triple screen). These tests serve as screens for structural fetal malformations and for neural tube closure defects. The triple screen also can detect some cases of Down syndrome, although there is a significant false-positive and false-negative rate.
More-invasive tests include amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, and, upon rare occasion, preimplantation testing of either a polar body or a dissected embryonic cell. Amniocentesis is a procedure in which a long, thin needle is inserted through the abdomen and uterus into the amniotic sac, enabling the removal of a small amount of the amniotic fluid bathing the fetus. This procedure is generally performed under ultrasound guidance between the 15th and 17th weeks of pregnancy, and, although it is generally regarded as safe, complications can occur, ranging from cramping to infection or loss of the fetus. The amniotic fluid obtained can be used in each of three ways: (1) living fetal cells recovered from this fluid can be induced to grow and can be analyzed to assess chromosome number, composition, or structure; (2) cells recovered from the fluid can be used for molecular studies; and (3) the amniotic fluid itself can be analyzed biochemically to determine the relative abundance of a variety of compounds associated with normal or abnormal fetal metabolism and development. Amniocentesis is typically offered to pregnant women over age 35, because of the significantly increased rate of chromosome disorders observed in the children of older mothers. A clear advantage of amniocentesis is the wealth of material obtained and the relative safety of the procedure. The disadvantage is timing: results may not be received until the pregnancy is already into the 19th week or beyond, at which point the possibility of termination may be much more physically and emotionally wrenching than if considered earlier.
Genetic testing
In the case of genetic disease, options often exist for presymptomatic diagnosis—that is, diagnosis of individuals at risk for developing a given disorder, even though at the time of diagnosis they may be clinically healthy. Options may even exist for carrier testing, studies that determine whether an individual is at increased risk of having a child with a given disorder, even though he or she personally may never display symptoms. Accurate predictive information can enable early intervention, which often prevents the clinical onset of symptoms and the irreversible damage that may have already occurred by waiting for symptoms and then responding to them. In the case of carrier testing, accurate information can enable prospective parents to make more-informed family-planning decisions. Unfortunately, there can also be negative aspects to early detection, including such issues as privacy, individual responses to potentially negative information, discrimination in the workplace, or discrimination in access to or cost of health or life insurance. While some governments have outlawed the use of presymptomatic genetic testing information by insurance companies and employers, others have embraced it as a way to bring spiraling health-care costs under control. Some communities have even considered instituting premarital carrier testing for common disorders in the populace.Genetic testing procedures can be divided into two different groups: (1) testing of individuals considered at risk from phenotype or family history and (2) screening of entire populations, regardless of phenotype or personal family history, for evidence of genetic disorders common in that population. Both forms are currently pursued in many societies. Indeed, with the explosion of information about the human genome and the increasing identification of potential “risk genes” for common disorders, such as cancer, heart disease, or diabetes, the role of predictive genetic screening in general medical practice is likely to increase.
At present, adults are generally tested for evidence of genetic disease only if personal or family history suggests they are at increased risk for a given disorder. A typical example would be a young man whose father, paternal aunt, and older brother have all been diagnosed with early onset colorectal cancer. Although this person may appear perfectly healthy, he is at significantly increased risk to carry mutations associated with familial colorectal cancer, and accurate genetic testing could enable heightened surveillance (e.g., frequent colonoscopies) that might ultimately save his life.
Carrier testing for adults in most developed nations is generally offered only if family history or ethnic origins suggest an increased risk of having a particular disease. A typical example would be to offer carrier testing for cystic fibrosis to a couple including one member who has a sibling with the disorder. Another would be to offer carrier testing for Tay-Sachs disease to couples of Ashkenazic Jewish origin, a population known to carry an increased frequency of Tay-Sachs mutations. The same would be true for couples of African or Mediterranean descent with regard to sickle cell anemia or thalassemia, respectively. Typically, in each of these cases a genetic counselor would be involved to help the individuals or couples understand their options and make informed decisions.
genetic screening, gene therapy, genome editing, carrier testing, personalized medicine, prenatal diagnosis, genetic counseling, CRISPR technology, pharmacogenomics, biomarkers, epigenetics, molecular diagnostics, genetic risk factors, family history, gene mutation, next-generation sequencing, rare diseases, therapeutic cloning, stem cell therapy, bioinformatics
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