genetic disease, human


genetic disease, human

Introduction

      any of the diseases and disorders that are caused by mutations in one or more genes (gene).

      With the increasing ability to control infectious and nutritional diseases in developed countries, there has come the realization that genetic diseases are a major cause of disability, death, and human tragedy. Rare, indeed, is the family that is entirely free of any known genetic disorder. Many thousands of different genetic disorders with defined clinical symptoms have been identified. Of the 3 to 6 percent of newborns with a recognized birth defect, at least half involve a predominantly genetic contribution. Furthermore, genetic defects are the major known cause of pregnancy loss in developed nations, and almost half of all spontaneous abortions (miscarriages (miscarriage)) involve a chromosomally abnormal fetus. About 30 percent of all postnatal infant mortality in developed countries is due to genetic disease; 30 percent of pediatric and 10 percent of adult hospital admissions can be traced to a predominantly genetic cause. Finally, medical investigators estimate that genetic defects—however minor—are present in at least 10 percent of all adults. Thus, these are not rare events.

      A congenital defect (congenital disorder) is any biochemical, functional, or structural abnormality that originates prior to or shortly after birth. It must be emphasized that birth defects do not all have the same basis, and it is even possible for apparently identical defects in different individuals to reflect different underlying causes. Though the genetic and biochemical bases for most recognized defects are still uncertain, it is evident that many of these disorders result from a combination of genetic and environmental factors.

      This article surveys the main categories of genetic disease, focusing on the types of genetic mutations that give rise to them, the risks associated with exposure to certain environmental agents, and the course of managing genetic disease through counseling, diagnosis, and treatment. For full explanation of Mendelian and non-Mendelian genetics, genetic mutation and regulation, and other principles underlying genetic disease, see the article heredity. The genetics of tumour development, briefly explained in this article, are covered at length in the article cancer.

Classes of genetic disease
      Most human genetic defects can be categorized as resulting from either chromosomal, single-gene Mendelian, single-gene non-Mendelian, or multifactorial causes. Each of these categories is discussed briefly below.

Diseases caused by chromosomal aberrations (chromosomal disorder)
      About 1 out of 150 live newborns has a detectable chromosomal abnormality. Yet even this high incidence represents only a small fraction of chromosome mutations since the vast majority are lethal and result in prenatal death or stillbirth. Indeed, 50 percent of all first-trimester miscarriages (miscarriage) and 20 percent of all second-trimester miscarriages are estimated to involve a chromosomally abnormal fetus.

      Chromosome disorders can be grouped into three principal categories: (1) those that involve numerical abnormalities of the autosomes, (2) those that involve structural abnormalities of the autosomes, and (3) those that involve the sex chromosomes (sex chromosome). Autosomes are the 22 sets of chromosomes found in all normal human cells. They are referred to numerically (e.g., chromosome 1, chromosome 2) according to a traditional sort order based on size, shape, and other properties. Sex chromosomes make up the 23rd pair of chromosomes in all normal human cells and come in two forms, termed X and Y. In humans and many other animals, it is the constitution of sex chromosomes that determines the sex of the individual, such that XX results in a female and XY results in a male.

Numerical abnormalities
      Numerical abnormalities, involving either the autosomes or sex chromosomes, are believed generally to result from meiotic nondisjunction—that is, the unequal division of chromosomes between daughter cells—that can occur during either maternal or paternal gamete formation. Meiotic nondisjunction leads to eggs or sperm with additional or missing chromosomes. Although the biochemical basis of numerical chromosome abnormalities remains unknown, maternal age clearly has an effect, such that older women are at significantly increased risk to conceive and give birth to a chromosomally abnormal child. The risk increases with age in an almost exponential manner, especially after age 35, so that a pregnant woman age 45 or older has between a 1 in 20 and 1 in 50 chance that her child will have trisomy 21 ( Down syndrome), while the risk is only 1 in 400 for a 35-year-old woman and less than 1 in 1,000 for a woman under the age of 30. There is no clear effect of paternal age on numerical chromosome abnormalities.

      Although Down syndrome is probably the best-known and most commonly observed of the autosomal trisomies, being found in about 1 out of 800 live births, both trisomy 13 and trisomy 18 are also seen in the population, albeit at greatly reduced rates (1 out of 10,000 live births and 1 out of 6,000 live births, respectively). The vast majority of conceptions involving trisomy for any of these three autosomes are nonetheless lost to miscarriage, as are all conceptions involving trisomy for any of the other autosomes. Similarly, monosomy for any of the autosomes is lethal in utero and therefore is not seen in the population. Because numerical chromosomal abnormalities generally result from independent meiotic events, parents who have one pregnancy with a numerical chromosomal abnormality are generally not at markedly increased risk above the general population to repeat the experience. Nonetheless, a small increased risk is generally cited for these couples to account for unusual situations, such as chromosomal translocations or gonadal mosaicism, described below.

Structural abnormalities
      Structural abnormalities of the autosomes are even more common in the population than are numerical abnormalities and include translocations of large pieces of chromosomes, as well as smaller deletions, insertions, or rearrangements. Indeed, about 5 percent of all cases of Down syndrome result not from classic trisomy 21 but from the presence of excess chromosome 21 material attached to the end of another chromosome as the result of a translocation event. If balanced, structural chromosomal abnormalities may be compatible with a normal phenotype, although unbalanced chromosome structural abnormalities can be every bit as devastating as numerical abnormalities. Furthermore, because many structural defects are inherited from a parent who is a balanced carrier, couples who have one pregnancy with a structural chromosomal abnormality generally are at significantly increased risk above the general population to repeat the experience. Clearly, the likelihood of a recurrence would depend on whether a balanced form of the structural defect occurs in one of the parents.

      Even a small deletion or addition of autosomal material—too small to be seen by normal karyotyping methods—can produce serious malformations and mental retardation (intellectual disability). One example is cri du chat (cri-du-chat syndrome) (French: “cry of the cat”) syndrome, which is associated with the loss of a small segment of the short arm of chromosome 5. Newborns with this disorder have a “mewing” cry like that of a cat. Mental retardation is usually severe.

Abnormalities of the sex chromosomes
      About 1 in 400 male and 1 in 650 female live births demonstrate some form of sex chromosome abnormality, although the symptoms of these conditions are generally much less severe than are those associated with autosomal abnormalities. Turner syndrome (Turner's syndrome) is a condition of females who, in the classic form, carry only a single X chromosome (45,X). Turner syndrome is characterized by a collection of symptoms, including short stature, webbed neck, and incomplete or absent development of secondary sex characteristics, leading to infertility. Although Turner syndrome is seen in about 1 in 2,500 to 1 in 5,000 female live births, the 45,X karyotype accounts for 10 to 20 percent of the chromosomal abnormalities seen in spontaneously aborted fetuses, demonstrating that almost all 45,X conceptions are lost to miscarriage. Indeed, the majority of liveborn females with Turner syndrome are diagnosed as mosaics, meaning that some proportion of their cells are 45,X while the rest are either 46,XX or 46,XY. The degree of clinical severity generally correlates inversely with the degree of mosaicism, so that females with a higher proportion of normal cells will tend to have a milder clinical outcome.

 In contrast to Turner syndrome, which results from the absence of a sex chromosome, three alternative conditions result from the presence of an extra sex chromosome: Klinefelter syndrome, trisomy X, and 47,XYY syndrome. These conditions, each of which occurs in about 1 in 1,000 live births, are clinically mild, perhaps reflecting the fact that the Y chromosome carries relatively few genes, and, although the X chromosome is gene-rich, most of these genes become transcriptionally silent in all but one X chromosome in each somatic cell (i.e., all cells except eggs and sperm) via a process called X inactivation. The phenomenon of X inactivation prevents a female who carries two copies of the X chromosome in every cell from expressing twice the amount of gene products encoded exclusively on the X chromosome, in comparison with males, who carry a single X. In brief, at some point in early development one X chromosome in each somatic cell of a female embryo undergoes chemical modification and is inactivated so that gene expression no longer occurs from that template. This process is apparently random in most embryonic tissues, so that roughly half of the cells in each somatic tissue will inactivate the maternal X while the other half will inactivate the paternal X. Cells destined to give rise to eggs do not undergo X inactivation, and cells of the extra-embryonic tissues preferentially inactivate the paternal X, although the rationale for this preference is unclear. The inactivated X chromosome typically replicates later than other chromosomes, and it physically condenses to form a Barr body, a small structure found at the rim of the nucleus in female somatic cells between divisions (see photograph—>). The discovery of X inactivation is generally attributed to British geneticist Mary Lyon, and it is therefore often called “lyonization.”

      The result of X inactivation is that all normal females are mosaics with regard to this chromosome, meaning that they are composed of some cells that express genes only from the maternal X chromosome and others that express genes only from the paternal X chromosome. Although the process is apparently random, not every female has an exact 1:1 ratio of maternal to paternal X inactivation. Indeed, studies suggest that ratios of X inactivation can vary. Furthermore, not all genes on the X chromosome are inactivated; a small number escape modification and remain actively expressed from both X chromosomes in the cell. Although this class of genes has not yet been fully characterized, aberrant expression of these genes has been raised as one possible explanation for the phenotypic abnormalities experienced by individuals with too few or too many X chromosomes.

      Klinefelter syndrome (Klinefelter's syndrome) (47,XXY) occurs in males and is associated with increased stature and infertility. gynecomastia (i.e., partial breast development in a male) is sometimes also seen. Males with Klinefelter syndrome, like normal females, inactivate one of their two X chromosomes in each cell, perhaps explaining, at least in part, the relatively mild clinical outcome.

      Trisomy X (X-trisomy) (47,XXX) is seen in females and is generally also considered clinically benign, although menstrual irregularities or sterility have been noted in some cases. Females with trisomy X inactivate two of the three X chromosomes in each of their cells, again perhaps explaining the clinically benign outcome.

      47,XYY syndrome also occurs in males and is associated with tall stature but few, if any, other clinical manifestations. There is some evidence of mild learning disability associated with each of the sex chromosome trisomies, although there is no evidence of mental retardation in these persons.

      Persons with karyotypes of 48,XXXY or 49,XXXXY have been reported but are extremely rare. These individuals show clinical outcomes similar to those seen in males with Klinefelter syndrome but with slightly increased severity. In these persons the “n − 1 rule” for X inactivation still holds, so that all but one of the X chromosomes present in each somatic cell is inactivated.

Diseases associated with single-gene Mendelian inheritance
      The term Mendelian is often used to denote patterns of genetic inheritance similar to those described for traits in the garden pea by Gregor Mendel (Mendel, Gregor) in the 1860s. Disorders associated with single-gene Mendelian inheritance are typically categorized as autosomal dominant, autosomal recessive, or sex-linked. Each category is described briefly in this section. For a full explanation of Mendelian genetics and of the concepts of dominance and recessiveness, see the article heredity.

Autosomal dominant inheritance (dominance)
 A disease trait that is inherited in an autosomal dominant manner can occur in either sex and can be transmitted by either parent. It manifests itself in the heterozygote (designated Aa), who receives a mutant gene (designated a) from one parent and a normal (“wild-type”) gene (designated A) from the other. In such a case the pedigree (i.e., a pictorial representation of family history) is vertical—that is, the disease passes from one generation to the next. The figure—> illustrates the pedigree for a family with achondroplasia, an autosomal dominant disorder characterized by short-limbed dwarfism that results from a specific mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. In pedigrees of this sort, circles refer to females and squares to males; two symbols directly joined at the midpoint represent a mating, and those suspended from a common overhead line represent siblings, with descending birth order from left to right. Solid symbols represent affected individuals, and open symbols represent unaffected individuals. The Roman numerals denote generations, whereas the Arabic numerals identify individuals within each generation. Each person listed in a pedigree may therefore be specified uniquely by a combination of one Roman and one Arabic numeral, such as II-1.

      An individual who carries one copy of a dominant (dominance) mutation (Aa) will produce two kinds of germ cells—eggs or sperm—typically in equal proportions; one half will bear the mutant gene (A), and the other will bear the normal gene (a). As a result, an affected heterozygote has a 50 percent chance of passing on the disease gene to each of his or her children. If an individual were to carry two copies of the dominant mutant gene (inherited from both parents), he or she would be homozygous (homozygote) (AA). The homozygote for a dominantly inherited abnormal gene may be equally affected with the heterozygote. Alternatively, he or she may be much more seriously affected; indeed, the homozygous condition may be lethal, sometimes even in utero or shortly after birth. Such is the case with achondroplasia, so that a couple with one affected partner and one unaffected partner will typically see half of their children affected, whereas a couple with both partners affected will see two-thirds of their surviving children affected and one-third unaffected, because 1 out of 4 conceptions will produce a homozygous fetus who will die before or shortly after birth.

       Human disorders attributable to a single dominant geneAlthough autosomal dominant traits are typically evident in multiple generations of a family, they can also arise from new mutations, so that two unaffected parents, neither of whom carries the mutant gene in their somatic cells, can conceive an affected child. Indeed, for some disorders the new mutation rate is quite high; almost 7 out of 8 children with achondroplasia are born to two unaffected parents. Examples of autosomal dominant inheritance are common among human traits and diseases. More than 2,000 of these traits have been clearly identified; a sampling is given in the table (Human disorders attributable to a single dominant gene).

      In many genetic diseases, including those that are autosomal dominant, specific mutations associated with the same disease present in different families may be uniform, such that every affected individual carries exactly the same molecular defect (allelic homogeneity), or they may be heterogeneous, such that tens or even hundreds of different mutations, all affecting the same gene, may be seen in the affected population (allelic heterogeneity). In some cases even mutations in different genes can lead to the same clinical disorder (genetic heterogeneity). Achondroplasia is characterized by allelic homogeneity, such that essentially all affected individuals carry exactly the same mutation.

      With regard to the physical manifestations (i.e., the phenotype) of some genetic disorders, a mutant gene may cause many different symptoms and may affect many different organ systems (pleiotropy). For example, along with the short-limbed dwarfism characteristic of achondroplasia, some individuals with this disorder also exhibit a long, narrow trunk, a large head with frontal bossing, and hyperextensibility of most joints, especially the knees. Similarly, for some genetic disorders, clinical severity may vary dramatically, even among affected members in the same family. These variations of phenotypic expression are called variable expressivity, and they are undoubtedly due to the modifying effects of other genes or environmental factors. Although for some disorders, such as achondroplasia, essentially all individuals carrying the mutant gene exhibit the disease phenotype, for other disorders some individuals who carry the mutant gene may express no apparent phenotypic abnormalities at all. Such unaffected individuals are called “nonpenetrant,” although they can pass on the mutant gene to their offspring, who could be affected.

Autosomal recessive inheritance
       Human disorders attributable to a single pair of recessive genesNearly 2,000 traits have been related to single genes that are recessive (recessiveness); that is, their effects are masked by normal (“wild-type”) dominant alleles and manifest themselves only in individuals homozygous for the mutant gene. A partial list of recessively inherited diseases is given in the table (Human disorders attributable to a single pair of recessive genes). For example, sickle cell anemia, a severe hemoglobin disorder, results only when a mutant gene (a) is inherited from both parents. Each of the latter is a carrier, a heterozygote with one normal gene and one mutant gene (Aa) who is phenotypically unaffected. The chance of such a couple producing a child with sickle cell anemia is one out of four for each pregnancy. For couples consisting of one carrier (Aa) and one affected individual (aa), the chance of their having an affected child is one out of two for each pregnancy.

      Many autosomal recessive traits reflect mutations in key metabolic enzymes and result in a wide variety of disorders classified as inborn errors of metabolism. One of the best-known examples of this class of disorders is phenylketonuria (PKU), which results from mutations in the gene encoding the enzyme phenylalanine hydroxylase (PAH). PAH normally catalyzes the conversion of phenylalanine, an amino acid prevalent in dietary proteins and in the artificial sweetener aspartame, to another amino acid called tyrosine. In persons with PKU, dietary phenylalanine either accumulates in the body or some of it is converted to phenylpyruvic acid, a substance that normally is produced only in small quantities. Individuals with PKU tend to excrete large quantities of this acid, along with phenylalanine, in their urine. When infants accumulate high concentrations of phenylpyruvic acid and unconverted phenylalanine in their blood and other tissues, the consequence is mental retardation. Fortunately, with early detection, strict dietary restriction of phenylalanine, and supplementation of tyrosine, mental retardation can be prevented.

 Since the recessive genes that cause inborn errors of metabolism are individually rare in the gene pool, it is not often that both parents are carriers; hence, the diseases are relatively uncommon. If the parents are related (consanguineous (consanguinity)), however, they will be more likely to have inherited the same mutant gene from a common ancestor. For this reason, consanguinity is often more common in the parents of those with rare, recessive inherited diseases. The pedigree of a family in which PKU has occurred is shown in the figure—>. This pedigree demonstrates that the affected individuals for recessive diseases are usually siblings in one generation—the pedigree tends to be “horizontal,” rather than “vertical” as in dominant inheritance.

Sex-linked inheritance
  Human disorders attributable to sex-linked recessive inheritanceIn humans, there are hundreds of genes located on the X chromosome that have no counterpart on the Y chromosome. The traits governed by these genes thus show sex-linked inheritance. This type of inheritance has certain unique characteristics, which include the following: (1) There is no male-to-male (father-to-son) transmission, since sons will, by definition, inherit the Y rather than the X chromosome. (2) The carrier female (heterozygote) has a 50 percent chance of passing the mutant gene to each of her children; sons who inherit the mutant gene will be hemizygotes and will manifest the trait, while daughters who receive the mutant gene will be unaffected carriers. (3) Males with the trait will pass the gene on to all of their daughters, who will be carriers. (4) Most sex-linked traits are recessively inherited, so that heterozygous females generally do not display the trait. The table (Human disorders attributable to sex-linked recessive inheritance) lists some sex-linked conditions. The figure—> shows a pedigree of a family in which a mutant gene for hemophilia A, a sex-linked recessive disease, is segregating. Hemophilia A gained notoriety in early studies of human genetics because it affected at least 10 males among the descendants of Queen Victoria, who was a carrier.

      Hemophilia A, the most widespread form of hemophilia, results from a mutation in the gene encoding clotting factor VIII. Because of this mutation, affected males cannot produce functional factor VIII, so that their blood fails to clot properly, leading to significant and potentially life-threatening loss of blood after even minor injuries. Bleeding into joints commonly occurs as well and may be crippling. Therapy consists of avoiding trauma and of administering injections of purified factor VIII, which was once isolated from outdated human blood donations but can now be made in large amounts through recombinant DNA technology.

      Although heterozygous female carriers of X-linked recessive mutations generally do not exhibit traits characteristic of the disorder, cases of mild or partial phenotypic expression in female carriers have been reported, resulting from nonrandom X inactivation.

Diseases associated with single-gene non-Mendelian inheritance
      Although disorders resulting from single-gene defects that demonstrate Mendelian inheritance are perhaps better understood, it is now clear that a significant number of single-gene diseases also exhibit distinctly non-Mendelian patterns of inheritance. Among these are such disorders that result from triplet repeat expansions within or near specific genes (e.g., Huntington disease and fragile-X syndrome); a collection of neurodegenerative disorders, such as Leber hereditary optic neuropathy (LHON), that result from inherited mutations in the mitochondrial DNA; and diseases that result from mutations in imprinted genes (e.g., Angelman syndrome and Prader-Willi syndrome).

Triplet repeat expansions
 At least a dozen different disorders are now known to result from triplet repeat expansions in the human genome, and these fall into two groups: (1) those that involve a polyglutamine tract within the encoded protein product that becomes longer upon expansion of a triplet repeat, an example of which is Huntington disease, and (2) those that have unstable triplet repeats in noncoding portions of the gene that, upon expansion, interfere with appropriate expression of the gene product, an example of which is fragile-X syndrome (see photograph—>). Both groups of disorders exhibit a distinctive pattern of non-Mendelian inheritance termed anticipation, in which, following the initial appearance of the disorder in a given family, subsequent generations tend to show both increasing frequency and increasing severity of the disorder. This phenotypic anticipation is paralleled by increases in the relevant repeat length as it is passed from one generation to the next, with increasing size leading to increasing instability, until a “full expansion” mutation is achieved, generally several generations following the initial appearance of the disorder in the family. The full expansion mutation is then passed to subsequent generations in a standard Mendelian fashion—for example, autosomal dominant for Huntington disease and sex-linked for fragile-X syndrome.

Mitochondrial DNA mutations
      Disorders resulting from mutations in the mitochondrial genome demonstrate an alternative form of non-Mendelian inheritance, termed maternal inheritance, in which the mutation and disorder are passed from mothers—never from fathers—to all of their children. The mutations generally affect the function of the mitochondrion, compromising, among other processes, the production of cellular adenosine triphosphate (ATP). Severity and even penetrance can vary widely for disorders resulting from mutations in the mitochondrial DNA, generally believed to reflect the combined effects of heteroplasmy (i.e., mixed populations of both normal and mutant mitochondrial DNA in a single cell) and other confounding genetic or environmental factors. There are close to 50 mitochondrial genetic diseases currently known.

Imprinted gene mutations (mutation)
      Some genetic disorders are now known to result from mutations in imprinted genes. Genetic imprinting involves a sex-specific process of chemical modification to the imprinted genes, so that they are expressed unequally, depending on the sex of the parent of origin. So-called maternally imprinted genes are generally expressed only when inherited from the father, and so-called paternally imprinted genes are generally expressed only when inherited from the mother. The disease gene associated with Prader-Willi syndrome is maternally imprinted, so that although every child inherits two copies of the gene (one maternal, one paternal), only the paternal copy is expressed. If the paternally inherited copy carries a mutation, the child will be left with no functional copies of the gene expressed, and the clinical traits of Prader-Willi syndrome will result. Similarly, the disease gene associated with Angelman syndrome is paternally imprinted, so that although every child inherits two copies of the gene, only the maternal copy is expressed. If the maternally inherited copy carries a mutation, the child again will be left with no functional copies of the gene expressed, and the clinical traits of Angelman syndrome will result. Individuals who carry the mutation but received it from the “wrong” parent can certainly pass it on to their children, although they will not exhibit clinical features of the disorder.

      Upon rare occasion, persons are identified with an imprinted gene disorder who show no family history and do not appear to carry any mutation in the expected gene. These cases are now known to result from uniparental disomy, a phenomenon whereby a child is conceived who carries the normal complement of chromosomes but who has inherited both copies of a given chromosome from the same parent, rather than one from each parent, as is the normal fashion. If any key genes on that chromosome are imprinted in the parent of origin, the child may end up with no expressed copies, and a genetic disorder may result. Similarly, other genes may be overexpressed in cases of uniparental disomy, perhaps also leading to clinical complications. Finally, uniparental disomy can account for very rare instances whereby two parents, only one of whom is a carrier of an autosomal recessive mutation, can nonetheless have an affected child, in the circumstance that the child inherits two mutant copies from the carrier parent.

Diseases caused by multifactorial inheritance
      Genetic disorders that are multifactorial in origin represent probably the single largest class of inherited disorders affecting the human population. By definition, these disorders involve the influence of multiple genes, generally acting in concert with environmental factors. Such common conditions as cancer, heart disease, and diabetes are now considered to be multifactorial disorders. Indeed, improvements in the tools used to study this class of disorders have enabled the assignment of specific contributing gene loci to a number of common traits and disorders. Identification and characterization of these contributing genetic factors may not only enable improved diagnostic and prognostic indicators but may also identify potential targets for future therapeutic intervention.

       Human disorders attributable to multifactorial inheritanceThe table (Human disorders attributable to multifactorial inheritance) lists some conditions associated with multifactorial inheritance. Because the genetic and environmental factors that underlie multifactorial disorders are often unknown, the risks of recurrence are usually arrived at empirically. In general, it can be said that risks of recurrence are not as great for multifactorial conditions as for single-gene diseases and that the risks vary with the number of relatives affected and the closeness of their relationship. Moreover, close relatives of more severely affected individuals (e.g., those with bilateral cleft lip and cleft palate) are generally at greater risk than those related to persons with a less-severe form of the same condition (e.g., unilateral cleft lip).

Genetics of cancer
      Although at least 90 percent of all cancers (cancer) are sporadic, meaning that they do not seem to run in families, nearly 10 percent of cancers are now recognized as familial, and some are actually inherited in an apparently autosomal dominant manner. Cancer may therefore be considered a multifactorial disease, resulting from the combined influence of many genetic factors acting in concert with environmental insults (e.g., ultraviolet radiation, cigarette smoke, and viruses).

      Cancers, both familial and sporadic, generally arise from alterations in one or more of three classes of genes: oncogenes, tumour suppressor genes, and genes whose products participate in genome surveillance—for example, in DNA damage repair. All these functions are described in the article cancer. For familial cancers, affected members inherit one mutant copy of a gene that falls into one of the latter two classes. That mutation alone is not sufficient to cause cancer, but it predisposes individuals to the disease because they are now either more sensitive to spontaneous somatic mutations, as in the case of altered tumour suppressor genes (tumour suppressor gene), or are more prone to experience mutations, as in the case of impaired DNA repair enzymes. Of course, sporadic cancers can also arise from mutations in these same classes of genes, but because all of the mutations must arise in the individual de novo, as opposed to being inherited, they generally appear only later in life, and they do not run in families.

      Retinoblastoma, an aggressive tumour of the eye that typically occurs in childhood, offers perhaps one of the clearest examples of the interplay between inherited and somatic mutations in the genesis of cancer. Current data suggest that 60 to 70 percent of all cases of retinoblastoma are sporadic, while the rest are inherited. The relevant gene, RB, encodes a protein that normally functions as a suppressor of cell cycle progression and is considered a classic tumour suppressor gene. Children who inherit one mutant copy of the RB gene are at nearly 100 percent risk to develop retinoblastoma, because the probability that their one remaining functional RB gene will sustain a mutation in at least one retinal cell is nearly assured. In contrast, children who inherit two functional copies of the RB gene must experience two mutations at the RB locus in the same retinal cell in order to develop retinoblastoma; this is a very rare event. This “two-hit” hypothesis of retinoblastoma formation has provided a foundation upon which most subsequent theories of the genetic origins of familial cancer have been built.

      Recent studies of both breast and colorectal cancers have revealed that, like retinoblastoma, these cancers are predominantly sporadic, although a small proportion are clearly familial. Sporadic breast cancer generally appears late in life, while the familial forms can present much earlier, often before age 40. For familial breast cancer, inherited mutations in one of two specific genes, BRCA1 and BRCA2, account for at least half of the cases observed. The BRCA1 and BRCA2 genes both encode protein products believed to function in the pathways responsible for sensing and responding to DNA damage in cells. While a woman in the general population has about a 10 percent lifetime risk of developing breast cancer, half of all women with BRCA1 or BRCA2 mutations will develop breast cancer by age 50, and close to 90 percent will develop the disease by age 80. Women with BRCA1 mutations are also at increased risk to develop ovarian tumours. As with retinoblastoma, both men and women who carry BRCA1 or BRCA2 mutations, whether they are personally affected or not, can pass the mutated gene to their offspring, although carrier daughters are much more likely than carrier sons to develop breast cancer.

      Two forms of familial colorectal cancer, hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP), have also been linked to predisposing mutations in specific genes. Persons with familial HNPCC have inherited mutations in one or more of their DNA mismatch repair genes, predominantly MSH2 or MLH1. Similarly, persons with FAP carry inherited mutations in their APC genes, the protein product of which normally functions as a tumour suppressor. For individuals in both categories, the combination of inherited and somatic mutations results in a nearly 100 percent lifetime risk of developing colorectal cancer.

      Although most cancer cases are not familial, all are undoubtedly diseases of the genetic material of somatic cells. Studies of large numbers of both familial and sporadic cancers have led to the conclusion that cancer is a disease of successive mutations, acting in concert to deregulate normal cell growth, provide appropriate blood supply to the growing tumour, and ultimately enable tumour cell movement beyond normal tissue boundaries to achieve metastasis (i.e., the dissemination of cancer cells to other parts of the body).

      Many of the agents that cause cancer (e.g., X rays, certain chemicals) also cause mutations or chromosome abnormalities. For example, a large fraction of sporadic tumours (tumour) have been found to carry oncogenes (oncogene), altered forms of normal genes (proto-oncogenes) that have sustained a somatic “gain-of-function” mutation. An oncogene may be carried by a virus, or it can result from a chromosomal rearrangement, as is the case in chronic myelogenous leukemia, a cancer of the white blood cells characterized by the presence of the so-called Philadelphia chromosome in affected cells. The Philadelphia chromosome arises from a translocation in which one half of the long arm of chromosome 22 becomes attached to the end of the long arm of chromosome 9, creating the dominant oncogene BCR/abl at the junction point. The specific function of the BCR/abl fusion protein is not entirely clear. Another example is Burkitt lymphoma, in which a rearrangement between chromosomes places the myc gene from chromosome 8 under the influence of regulatory sequences that normally control expression of immunoglobulin genes. This deregulation of myc, a protein involved in mediating cell cycle progression, is thought to be one of the major steps in the formation of Burkitt lymphoma.

Cognitive and behavioral genetics (behaviour genetics)
      Mental activities, expressed in human behaviour, are intimately related to physical activities in the brain and nervous system. In 1929 British physician Sir Archibald Garrod emphasized this when he wrote:

Each one of us differs from his fellows, not only in bodily structure and the proteins which enter into his composite, but apart from, or rather in consequence of, such individualities, men differ in mental outlook, character and ability.

      Since that time, many investigators have sought to analyze the molecular and cellular components of behaviour in order to relate genes to such abstractions as intellect, temperament, and the emotions. Because the brain is ultimately responsible for behavioral development, neurobiologists have attempted to understand the unusual precision by which this organ's various regions are interconnected and the intricate chemical signals that, under genetic control, organize its complicated nerve fibre circuits.

      Some of the most powerful experiments to dissect the “nature versus nurture” aspects of human intelligence and behaviour have involved studies of twins (twin), both monozygotic (identical) and dizygotic (fraternal). Cognitive or behavioral characteristics that are entirely under genetic control would be predicted to be the same, or concordant, in monozygotic twins, who share identical genes regardless of their upbringing. These same characteristics would be predicted to be less concordant in dizygotic twins, who share, on average, only half of their genes. Comparison of the concordance rates among monozygotic and dizygotic twins monitored for different traits allows an estimate of the heritability of those traits—that is, the proportion of population variation for a given trait that can be attributed to genes. A heritability value of 1.0 implies a purely genetic basis for a trait, and a value of 0.0 implies a purely environmental basis. intelligence, measured as IQ, has a heritability value of 0.5, indicating that both genetics and environment play major roles in determining this trait. In contrast, schizophrenia has a value of 0.7, and both autism and bipolar disorder have heritability values of 1.0. Clearly, genetics play a large role in determining not only how our bodies look and function but also how we think and feel.

Genetic damage from environmental agents
      We are exposed to many agents, both natural and man-made, that can cause genetic damage. Among these agents are viruses; compounds produced by plants, fungi, and bacteria; industrial chemicals; products of combustion; alcohol; ultraviolet and ionizing radiation; and even the oxygen that we breathe. Many of these agents have long been unavoidable, and consequently human beings have evolved defenses to minimize the damage that they cause and ways to repair the damage that cannot be avoided.

Viruses (virus)
      Viruses (virus) survive by injecting their genetic material into living cells with the consequence that the biochemical machinery of the host cell is subverted from serving its own needs to serving the needs of the virus. During this process the viral genome often integrates itself into the genome of the host cell. This integration, or insertion, can occur either in the intergenic regions that make up the vast majority of human genomes, or it can occur in the middle of an important regulatory sequence or even in the region coding for a protein—i.e., a gene. In either of the latter two scenarios, the regulation or function of the interrupted gene is lost. If that gene encodes a protein that normally regulates cell division, the result may be unregulated cell growth and division. Alternatively, some viruses carry dominant oncogenes in their genomes, which can transform an infected cell and start it on the path toward cancer. Furthermore, viruses can cause mutations leading to cancer by the killing of the infected cell. Indeed, one of the body's defenses against viral infection involves recognizing and killing infected cells. The death of cells necessitates their replacement by the division of uninfected cells, and the more cell division that occurs, the greater the likelihood of a mutation arising from the small but finite infidelity in DNA replication. Among the viruses that can cause cancer are Epstein-Barr virus, papilloma viruses, hepatitis B and C viruses, retroviruses (e.g., human immunodeficiency virus), and herpes virus.

Plants (plant), fungi (fungus), and bacteria
      During the ongoing struggle for survival, organisms have evolved (evolution) toxic compounds as protection against predators or simply to gain competitive advantage. At the same time, these organisms have evolved mechanisms that make themselves immune to the effects of the toxins (toxin) that they produce. Plants in particular utilize this strategy since they are rooted in place and cannot escape from predators. One-third of the dry weight of some plants can be accounted for by the toxic compounds that are collectively referred to as alkaloids. Aspergillus flavus, a fungus that grows on stored grain and peanuts, produces a powerful carcinogen called aflatoxin that can cause liver cancer. Bacteria produce many proteins that are toxic to the infected host, such as diphtheria toxin. They also produce proteins called bacteriocins that are toxic to other bacteria. Toxins can cause mutations indirectly by causing cell death, which necessitates replacement by cell division, thus enhancing the opportunity for mutation. Cyanobacteria (blue-green algae) that grow in illuminated surface water produce several carcinogens, such as microcystin, saxitoxin, and cylindrospermopsin, that can also cause liver cancer.

Industrial chemicals
      Tens of thousands of different chemicals are routinely used in the production of plastics, fuels, food additives, and even medicines. Many of these chemicals are mutagens (mutagen), and some have been found to be carcinogenic (cancer-producing) in rats or mice. A relatively easy and inexpensive test for mutagenicity, the Ames test, utilizes mutant strains of the bacterium Salmonella typhimurium and can be completed in a few days. Testing for carcinogenesis, on the other hand, is very time-consuming and expensive because the test substance must be administered to large numbers of laboratory animals, usually mice, for months before the tissues can be examined for cancers. For this reason, the number of known mutagens far exceeds the number of known carcinogens. Furthermore, animal tests for carcinogenesis are not completely predictive of the effects of the test chemical on humans for several reasons. First, the abilities of laboratory animals and humans to metabolize and excrete specific chemicals can differ greatly. In addition, in order to avoid the need to test each chemical at a range of doses, each chemical is usually administered at the maximum tolerated dose. At such high doses, toxicity and cell death occur, necessitating cell replacement by growth and cell division; cell division, in turn, increases the opportunity for mutation and hence for cancer. Alternatively, unusually high doses of a chemical may actually mask the carcinogenic potential of a compound because damaged cells may die rather than survive in mutated form.

combustion products
      The burning of fossil fuels (fossil fuel) quite literally powers modern industrial societies. If the combustion of such fuels were complete, the products would be carbon dioxide and water. However, combustion is rarely complete, as is evidenced by the visible smoke issuing from chimneys and from the exhausts of diesel engines. Moreover, in addition to the particulates that we can see, incomplete combustion produces a witch's brew of volatile compounds that we do not see; and some of these, such as the dibenzodioxins, are intensely mutagenic and have been demonstrated to cause cancer in laboratory rodents. Epidemiological data indicate that dioxins are associated with increased risk of a variety of human cancers. The health consequences of combustion are further increased by impurities in fossil fuels and in the oxygen that supports their burning. For example, coal contains sulfur, mercury, lead, and other elements in addition to carbon. During combustion, sulfur becomes sulfur dioxide and that, in turn, gives rise to sulfurous and sulfuric acids. The mercury in the fuel is emitted as a vapour that is very toxic. Atmospheric nitrogen is oxidized at the high temperature of combustion.

      The smoke (smoking) from a cigarette, drawn directly into the lungs, imparts a large number of particulates, as well as a host of volatile compounds, directly into the airways and alveoli. Some of the volatile compounds are toxic in their own right and others, such as hydroquinones, slowly oxidize, producing genotoxic free radicals. As macrophages in the lungs attempt to engulf and eliminate particulates, they cause the production of mutagenic substances. A large fraction of lung cancers are attributable to cigarette smoking, which is also a risk factor for atherosclerosis, hypertension (high blood pressure), heart attack (myocardial infarction), and stroke.

      Moderate consumption of alcohol (ethanol) is well-tolerated and may even increase life span. However, alcohol is a potentially toxic substance and one of its metabolites, acetaldehyde, is a mild mutagen. Hence, it is not surprising that the chronic consumption of alcohol leads to liver cirrhosis and other untoward effects. Consumption of alcohol during pregnancy can cause fetal alcohol syndrome, which is characterized by low birth weight, mental retardation, and congenital heart disease.

      Due to human activities that result in the release of volatile halocarbon compounds, such as the refrigerant freon and the solvent carbon tetrachloride, the chlorine content of the upper atmosphere is increasing, and chlorine catalyzes the decomposition of ozone, which shields the Earth from ultraviolet radiation that is emitted from the Sun. The Earth's ozone shield has been progressively depleted, most markedly over the polar regions but also measurably so over the densely populated regions of northern Europe, Australia, and New Zealand. One consequence has been an increase in a variety of skin cancers, including melanoma, in those areas. Steps have been taken to stop the release of halocarbons, but the depletion of the ozone layer will nonetheless persist and may worsen for at least several decades.

      Ultraviolet light, when acting on DNA, can lead to covalent linking of adjacent pyrimidine bases. Such pyrimidine dimerization is mutagenic, but this damage can be repaired by an enzyme called photolyase, which utilizes the energy of longer wavelengths of light to cleave the dimers. However, people with a defect in the gene coding for photolyase develop xeroderma pigmentosum, a condition characterized by extreme sensitivity to sunlight. These individuals develop multiple skin cancers on all areas of exposed skin, such as the head, neck, and arms.

      Ultraviolet light can also be damaging because of photosensitization, the facilitation of photochemical processes. One way that photosensitizers work is by absorbing a photon and then transferring the energy inherent in that photon to molecular oxygen, thus converting the less-active ground-state molecular oxygen into a very reactive excited state, referred to as singlet oxygen, that can attack a variety of cellular compounds, including DNA. Diseases that have a photosensitizing component include lupus and porphyrias. In addition to photosensitizers that occur naturally in the human body, some foods and medicines (e.g., tetracycline) also act in this way, producing painful inflammation and blistering of the skin following even modest exposure to the sun.

Ionizing radiation (ionizing radiation injury)
      X rays (X-ray) and gamma rays are sufficiently energetic to cleave water into hydrogen atoms and hydroxyl radicals and are consequently referred to as ionizing radiation. Ionizing radiation and the products of the cleavage of water are able to damage all biological macromolecules, including DNA, proteins, and polysaccharides, and they have long been recognized as being mutagenic, carcinogenic, and lethal. People are routinely exposed to natural sources of ionizing radiation, such as cosmic rays, and to radioisotopes, such as carbon-14 and radon. They are also exposed to X rays and man-made radioisotopes used for diagnostic purposes, and some people have been exposed to radioactive fallout from nuclear weapon tests and reactor accidents. Such exposures would be much more damaging were it not for multiple mechanisms of DNA repair that have evolved to deal with simple errors in replication as well as with damage from naturally occurring sources.

Molecular oxygen
      Molecular oxygen (O2), although essential for life, must be counted among the environmental toxins and mutagens. Because of its unusual electronic structure, O2 is most easily reduced not by electron pairs but rather by single electrons added one at a time. As O2 is converted into water, superoxide (O2), hydrogen peroxide (H2O2), and a hydroxyl radical (HO∙) are produced as intermediates. O2 can initiate free-radical oxidation of important metabolites, inactivate certain enzymes, and cause release of iron from specific enzymes. The second intermediate, H2O2, is a strong oxidant and can give rise to an even more potent oxidant, namely HO∙, when it reacts with ferrous iron. Thus, O2 and H2O2 can collaborate in the formation of the destructive HO∙ and can subsequently lead to DNA damage, mutagenesis, and cell death. Breathing 100 percent oxygen causes damage to the alveoli, which leads to accumulation of fluid in the lungs. Thus, paradoxically, prolonged exposure to hyperoxia causes death due to lack of oxygen.

      Humans have evolved multiple defense systems to counter the toxicity and mutagenicity of O2. Thus, O2 is rapidly converted into O2 and H2O2 by a family of enzymes called superoxide dismutases. H2O2, in turn, is eliminated by other enzymes called catalases and peroxidases, which convert it into O2 and water.

      A few genetic diseases are known to be related to oxygen radicals or to the enzymes that defend against them. chronic granulomatous disease (CGD) is caused by a defect in the ability of the phagocytic leukocytes to mount the respiratory burst, part of the body's defense against infection. Upon contacting microorganisms and engulfing them, phagocytes greatly increase their consumption of O2 (the respiratory burst) while releasing O2, H2O2, hypochlorite (HOCl), and other agents that kill the microbe. The reduction of O2 to O2 is caused by a multicomponent enzyme called nicotine adenine dinucleotide phosphate (NADPH) oxidase. A defect in any of the components of this oxidase will lead to the absence of the respiratory burst, giving rise to the constant infections indicative of CGD. Before the discovery and clinical application of antibiotics, people born with CGD died from infection during early childhood.

      Another such genetic disease is a familial form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, which is characterized by late-onset progressive paralysis due to the loss of motor neurons. Approximately 20 percent of cases of ALS have been shown to result from mutations affecting the enzyme superoxide dismutase. The disease is genetically dominant, so that the mutant enzyme causes the disease even when half of the superoxide dismutase present in cells exists in the normal form. Interestingly, most of the mutant variants retain full catalytic activity.

Management of genetic disease
      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 (therapeutics) 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 (genetic disease, human). 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 (genetic disease, human).) 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 (genotype) 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).

      After determining the nature of the heredity, the counselor discusses with the consultand the likely risks and the available options to minimize impact of those risks on the individual and the family. In the case of a couple in which one member has a family history of a genetic disorder—for example, cystic fibrosis—typical options might include any of the following choices: (1) Accept the risks and take a chance that any future children may be affected. (2) Seek molecular testing for known mutations of cystic fibrosis in relevant family members to determine with greater accuracy whether either or both prospective parents are carriers for this recessive disorder. (3) If both members of the couple are determined to be carriers, utilize donor sperm for artificial insemination. This option is a good genetic solution only if the husband carries a dominant mutation, or if both parents are carriers of a recessive mutation. If the recessive trait is reasonably common, as are mutations for cystic fibrosis, however, it would be reasonable to ask that the sperm donor be checked for carrier status before pursuing this option. (4) Proceed with natural reproduction, but pursue prenatal diagnosis with the possibility of selective termination of an affected pregnancy, if desired by the parents. (5) Pursue in vitro fertilization with donor eggs, if the woman is the at-risk partner, or use both eggs and sperm from the couple but employ preimplantation diagnostics to select only unaffected embryos for implantation (see below). (6) Decide against biological reproduction because the risks and available options are unacceptable; possibly pursue adoption.

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.

      Chorionic villus sampling (CVS) is a procedure in which either a needle is inserted through the abdomen or a thin tube is inserted into the vagina and cervix to obtain a small sample of placental tissue called chorionic villi. CVS has the advantage of being performed earlier in the pregnancy (generally 10–11 weeks), although the risk of complications is greater than that for amniocentesis. Risks associated with CVS include fetal loss and fetal limb reduction if the procedure is performed earlier than 10 weeks gestation. Another disadvantage of CVS reflects the tissue sampled: chorionic villi are not part of the embryo, and such a sample may not accurately represent the embryonic genetic constitution. In contrast, amniotic cells are embryonic in origin, having been sloughed off into the fluid. Therefore, abnormalities, often chromosomal, may be seen in the chorionic villi but not in the fetus, or vice versa.

      Both percutaneous umbilical blood sampling (PUBS) and preimplantation testing are rare, relatively high-risk, and performed only in very unusual cases. Preimplantation testing of embryos derived by in vitro fertilization is a particularly new technique and is currently used only in cases of couples who are at high risk for having a fetus affected with a given familial genetic disorder and who find all other alternatives unacceptable. Preimplantation testing involves obtaining eggs and sperm from the couple, combining them in the laboratory, and allowing the resultant embryos to grow until they reach the early blastocyst stage of development, at which point a single cell is removed from the rest and harvested for fluorescent in situ hybridization (fluorescence in situ hybridization) (FISH) or molecular analysis. The problem with this procedure is that one cell is scant material for diagnosis, so that a large array of tests cannot be performed. Similarly, if the test fails for any technical reason, it cannot be repeated. Finally, embryos determined to be normal and therefore selected for implantation into the mother are subject to other complications normally associated with in vitro fertilization—namely, that only a small fraction of the implanted embryos make it to term and that multiple, and therefore high-risk, pregnancies are common. Nonetheless, many at-risk couples find these complications easier to accept than the elective termination of the pregnancy.

      It should be noted that researchers have identified fetal cells in the maternal circulation and that procedures are currently under development to enable their isolation and analysis, thereby providing a noninvasive alternative for molecular prenatal testing. Although these techniques are currently experimental and are not yet available for clinical application, they may well become the methods of choice in the future.

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.

      Screening of large unphenotyped populations for evidence of genetic disease is currently pursued in most industrialized nations only in the newborn population, although future developments in the identification of risk genes for common adult onset disorders may change this policy. So-called mandated newborn screening was initiated in many societies in the latter quarter of the 20th century in an effort to prevent the drastic and often irreversible damage associated with a small number of relatively common genetic disorders whose sequelae can be either prevented or significantly relieved by early detection and intervention. The general practice is to collect a small sample of blood from each newborn, generally by pricking the infant's heel and collecting drops of blood on special filter paper, which is then analyzed. Perhaps the best-known disorder screened in this manner is phenylketonuria (PKU), an autosomal recessive inborn error of metabolism discussed in the section Autosomal recessive inheritance. With early diagnosis and dietary intervention that is maintained throughout life, children with PKU can escape mental retardation and grow into healthy adults who lead full and productive lives. Although many of the genetic disorders currently tested by mandated newborn screening are metabolic in nature, this trend is beginning to change. For example, in some communities newborns are screened for profound congenital hearing loss, which is now known to be frequently genetic in origin and for which effective intervention is now available (e.g., through cochlear implants).

      Genetic tests themselves can take many forms, and the choice of tests depends on a number of factors. For example, screening for evidence of sickle cell anemia, a hemoglobin disorder, is generally pursued at least initially by tests involving the hemoglobin proteins themselves, rather than DNA, because the relevant gene product (blood) is readily accessible, and because the protein test is currently cheaper to perform than the DNA test. In contrast, screening for cystic fibrosis, a disorder that predominantly affects the lungs and pancreas, is generally pursued in the at-risk newborn at the level of DNA because there is no cheap and accurate alternative. Older persons suspected of having cystic fibrosis, however, can also be diagnosed with a “sweat test” that measures sweat electrolytes.

      Tests involving analysis of DNA are particularly powerful because they can be performed using very tiny samples; also, the DNA tested can originate from almost any tissue type, regardless of whether the gene of interest happens to be expressed in that tissue. Current technologies applied for mutation detection include traditional karyotyping and Southern blotting, as well as a multitude of new tests, including FISH with specific probes or the polymerase chain reaction (PCR), which refers to an enzymatic process by which specific regions of the genome can be amplified for molecular study. Which tests are applied depends on whether the genetic abnormalities are likely to be chromosomal (in which case karyotyping or FISH are appropriate), large deletions or other rearrangements (best tested for by Southern blotting or PCR), or point mutations (best confirmed by PCR followed by oligonucleotide hybridization or restriction enzyme digestion). If a large number of different point mutations are sought, as is often the case, the most appropriate technology may be microarray hybridization analysis, which can test for tens to hundreds of thousands of different point mutations in the same sample simultaneously.

Options for treatment (therapeutics)
      Options for the treatment of genetic disease are both many and expanding. Although a significant number of genetic diseases still have no effective treatment, for many the treatments are quite good. Current approaches include dietary management, such as the restriction of phenylalanine in PKU; protein or enzyme replacement, such as that used in Gaucher syndrome (Gaucher disease), hemophilia, and diabetes; and tissue replacement, such as blood transfusions (blood transfusion) or bone marrow transplantation in sickle cell anemia and thalassemia. Other treatments are strictly symptomatic, such as the use of splints in Ehlers-Danlos syndrome, administration of antibiotics in early cystic fibrosis, or female hormone replacement in Turner syndrome. Many options involve surveillance and surgery, such as regular checks of aortic root diameter followed by surgery to prevent aortic dissection in Marfan syndrome, or regular colonoscopies in persons at risk for familial colon cancer followed by surgical removal of the colon at the first signs of disease.

      Some genetic diseases may also be amenable to treatment by gene therapy, the introduction of normal genetic sequences to replace or augment the inherited gene whose mutation underlies the disease. Although some successes have been reported with gene therapy trials in humans—for example, with patients who have severe combined immunodeficiency (SCID) or hemophilia—significant technical challenges remain.

Ethical issues
      Our genetic constitution contributes to making us not only what we are—tall or short, male or female, healthy or sick—but also who we are, how we think and feel. Furthermore, although we generally like to think of our genomes as being uniquely ours, in fact we share significant aspects of them with our families, and information about our own genes is also information about our loved ones. Perhaps most important, in the biological sense, the genes we pass on to our children represent the closest we will ever come to immortality. For these reasons and others, human genetics is a topic fraught with ethical dilemma, with enormous power for good but also with frightening possibilities for misuse. The challenge and responsibility are to harness available information and technologies to improve life and health for all people without compromising privacy, autonomy, or diversity. Of vital importance in achieving these goals is an educated society that is aware of the advantages of new technologies yet is also concerned about their potential dangers.

Arthur Robinson Judith Fridovich-Keil Irwin Fridovich

Additional Reading
James Wynbrandt and Mark D. Ludman, The Encyclopedia of Genetic Disorders and Birth Defects, 2nd ed. (2000); Benjamin A. Pierce, The Family Genetic Sourcebook (1990); Karen Bellenir, Genetic Disorders Sourcebook (2000); and John F. Jackson, Genetics and You (1996), provide basic, easily understandable information on the principles of heredity and the causes, screening, and treatment of genetic disease. Raye Lynn Alford, Genetics and Your Health: A Guide for the 21st Century (1999), discusses recent advances in genetic research, including the Human Genome Project, and its effects on the diagnosis and treatment of genetic disease. Doris Teichler-Zallen, Does It Run in the Family? A Consumer's Guide to DNA Testing for Genetic Disorders (1997), explains the biochemical bases of genetic tests and various policy issues surrounding their use. Harold Varmus and Robert A. Weinberg, Genes and the Biology of Cancer (1993), explores the genetic basis of the disease.George H. Sack, Jr., Medical Genetics (1999); and Arthur P. Mange and Elaine Johansen Mange, Genetics: Human Aspects, 2nd ed. (1990), are informative, upper-level textbooks. Victor A. McKusick, Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders, 12th ed. (1998), is a compendium of human genes and the mutations that cause disease.

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Universalium. 2010.

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