genetic disorder

n.
A pathological condition caused by an absent or defective gene or by a chromosomal aberration. Also called hereditary disease, inherited disorder.

n

A disease that is caused by a defect or anomaly in the genetic inheritance of the patient.

The traditional method used to study an inherited disease is to observe the pattern of its distribution in families through examination of a pedigree, the construction of which begins with the individual first known to have the disease. The pedigree pattern allows one to judge whether or not the distribution conforms to Mendelian principles of segregation and assortment, and thus represents single-factor inheritance. Patterns that do not conform to Mendelian principles may represent polygenic traits, which represent the cumulative effects of a number of different genes. These complex patterns underlie the vast majority of human diseases.

Disorders caused by single mutant genes show one of four simple (Mendelian) patterns of inheritance: (1) autosomal dominant, (2) autosomal recessive, (3) X-linked dominant, or (4) X-linked recessive. A dominant trait is one that is expressed in the heterozygote (as well as in the homozygote or hemizygote). A recessive trait is one that is expressed in a homozygote (or a hemizygote), but silent in the heterozygote. The terms "dominant" and "recessive" refer to the phenotypic expression of a trait, not to the expression of the gene. Thus it is incorrect to speak of a dominant or recessive gene. A gene is either expressed or not expressed. Whether the trait is considered dominant or recessive often depends upon the level of observation. Sickle cell anemia is a recessive trait—it requires a double dose of the abnormal gene for expression at the clinical level. Nevertheless, the sickle gene can be expressed in single dose as well, giving rise to carriers with SA hemoglobin. In a state of reduced oxygen tension, red cells in SA carriers may sickle. Recessive traits may thus be codominant when viewed biochemically at the level of the gene product, or dominant in an altered environment.

Autosomal Dominant Traits

By definition, genes that are situated on chromosomes other than the X or Y sex chromosomes are autosomal. Dominant traits are fully evident when only one abnormal gene (mutant allele) is present and the corresponding partner allele on the homologous chromosome is normal (a heterozygous state). The representative initial for the dominant gene is typically capitalized, and the recessive gene is placed in lower case. Thus, if there are two alleles of a given gene that are referred to as "A" and "a," three possible genotypes exist: AA, Aa, and aa. Genotypes AA and aa are homozygotes; Aa is a heterozygote.

Autosomal dominant traits bear the following characteristic features: (1) an affected individual usually bears an equal number of affected and unaffected offspring; (2) unless the condition arose by a new mutation in a germ cell that formed the individual, each affected individual has an affected parent; (3) males and females are affected in equal numbers; (4) each gender can transmit the trait to male and female; (5) normal children of an affected individual have only normal offspring; and (6) when the trait does not impair viability or reproductive capacity, vertical transmission of the trait occurs through successive generations. The best evidence of a dominant trait is three or more generations of male-to-male transmission.

Autosomal dominant disorders often show two additional characteristics that are rarely seen in recessive disorders: (1) marked variability in the severity, or expressivity, of the disorder and (2) delayed age of onset. In heterozygotes the expression of the abnormal gene can be so weak that a generation appears to be skipped because the carrier of the abnormal gene is clinically normal. In such fortunate individuals, the trait is said to be "nonpenetrant." In some diseases, such as Huntington's disease and adult polycystic kidney disease, the disorder may not become manifest clinically until adult life, even though the mutant gene has been present since conception.

In every autosomal dominant disease, some affected persons owe their disorder to a new mutation rather than to an inherited allele. A reasonable estimate of the frequency of mutation is on the order of 5 × 10^-6 mutations per allele per generation. Because a dominant trait requires a mutation in only one of the parental gametes, the expected frequency for a new autosomal dominant disease in any given gene is one in 100,000 newborns.

A classic example of a dominant trait in humans is familial hypercholesterolemia, an autosomal dominant disorder characterized by elevation of serum cholesterol bound to low-density lipoprotein (LDL). Mutations in the LDL receptor (LDLR) gene on chromosome 19 cause the disorder. Heterozygotes develop fatty collections on their tendons, a corneal arc, and, of greatest concern, coronary artery disease, which typically presents in the fourth or fifth decade of life. Homozygotes develop these features at an accelerated rate. In the United States, the frequency of homozygotes is approximately one in a million, and the frequency of heterozygotes is approximately one in five hundred. However, among patients with a history of myocardial infarction (heart attacks), the heterozygote frequency is about one in twenty.

Autosomal Recessive Disorders

Autosomal recessive conditions are clinically apparent only in the homozygous state—when both alleles at a particular genetic locus are deleterious. In most autosomal recessive disorders the clinical presentation tends to be more uniform than in dominant diseases, and the onset is often early in life. The following features are characteristic: (1) on average, male and female siblings are affected in equal proportions; (2) the parents are clinically normal; (3) all of the children of the union between an affected individual and a homozygous normal individual are heterozygous carriers, but none will be affected; (4) on average, half of the children are affected when an affected individual mates with a heterozygous carrier (a pseudo-dominant pedigree); (5) all of the children of a union between two individuals homozygous for the same mutant gene will be affected; (6) on average, if both parents are heterozygous at the same genetic locus, one-fourth of their children are homozygous affected, one-fourth are homozygous normal, and half are heterozygous carriers of the same mutant gene; and (7) the less frequent the mutant gene is in the population, the greater the likelihood that the affected individual is the product of consanguineous parents.

Consanguinity increases the likelihood of a child presenting with a recessive disease because the likelihood of inheriting the same rare mutation from a distant common ancestor, or "founder" increases. First cousins share, on the average, one-eighth of their genes. When two first cousins marry, an offspring has, on average, one-sixteenth of the loci homozygous for a gene derived from a common ancestor. In general, offspring of first cousins are slightly more likely to have congenital malformations, as well as mental defects and metabolic diseases, than are children born to unrelated parents.

Increased frequency of consanguinity is not observed if the recessive disease is common. Cystic fibrosis exemplifies an autosomal recessive disorder that is common among individuals of Northern European descent. In the United States, the frequency of individuals heterozygous for a mutation in the cystic fibrosis conductance regulator gene (CFTR) is quoted as one in twenty-five. Inheritance of two malfunctioning genes leads to the disruption of pancreatic exocrine function and chronic bronchitis with emphysema, as well as biliary cirrhosis, meconium ileus, and an enhanced loss of salt through the skin, which is the basis of the "sweat test" used for screening purposes. The frequency of individuals affected with cystic fibrosis is one in 2,500, and typically the parents are unrelated.

X-Linked Inheritance

Diseases or traits that result from genes located on the X chromosome are termed "X-LINKED." Because the female has two X chromosomes, she may be either heterozygous or homozygous for the mutant gene, and the trait may exhibit recessive or dominant expression. The terms "X-LINKED dominant" and "X-LINKED recessive" refer only to expression of the trait in females. The male has only one X chromosome and therefore is hemizygous for X-linked traits. Males can be expected to express X-linked traits regardless of their recessive or dominant behavior in the female. This accounts for the large numbers of X-linked diseases. Affected males do not transmit an X chromosome to their sons; thus an important feature of X-linked inheritance is the absence of male-to-male transmission. In contrast, since all females inherit their fathers' single X chromosomes, their daughters are all obligate carriers.

Although genotypically females have two X chromosomes, functionally they behave as though they only have one X chromosome, like their brothers. This is due to the process of X-inactivation, which was first proposed by Mary Lyon and is termed "lyonization" in her honor. During ontogeny, one of the X chromosomes becomes inactive, condensing to form a "Barr body." Inactivation is random, so each cell has an equal probability that the paternally or maternally derived X chromosome will be inactivated. Once one of the two X chromosomes is inactivated, the same X chromosome remains inactive throughout all subsequent cell divisions. Thus, on average, half of the cells of a female express the X chromosome of her father and half of her mother.

For the vast majority of genes on the X chromosome, the normal female is a mosaic, with her cells expressing one or the other X chromosome, but not necessarily a 50–50 mosaic. Inactivation of one of the X chromosomes occurs early in development and is random; hence many females may, by chance, have many more cells that carry an active X chromosome derived from one parent than from the other. Similarly, if one of the X chromosomes carries a mutant gene that confers a metabolic disadvantage upon cells with that mutation, these cells may survive less frequently during development, and the female offspring may have cells that carry predominantly or exclusively the active X chromosome without the mutation.

X-linked dominant traits are uncommon. The characteristic features are as follows: (1) females are affected about twice as often as males; (2) heterozygous females transmit the trait to both genders with a frequency of 50 percent; (3) hemizygous affected males transmit the trait to all of their daughters and none of their sons; and (4) the expression is more variable and generally less severe in heterozygous females than in hemizygous affected males. Some rare X-linked dominant disorders occur only in the heterozygous female, because the condition is lethal in the hemizygous affected male. Additional characteristics of this form of inheritance are as follows: (1) an affected mother transmits the trait to half of her daughters (heterozygotes), and (2) an increased frequency of abortions occurs in affected women, the abortions representing affected male fetuses.

X-linked recessive traits are relatively common. The characteristic features are as follows:(1) the disorder is fully expressed only in the hemizygous affected male; (2) heterozygous females are usually normal, although occasionally they may exhibit mild features of the disorder, and in females who have unfortunately inactivated the wrong X chromosome may be almost as severely affected as the hemizygous affected male; (3) on average, a heterozygous female transmits the trait to half of her sons (hemizygous affected), but the other half are normal; (4) on average, half of the daughters of a heterozygous female are carriers and half are normal; (5) all daughters of an affected male and a normal female are carriers, and no sons of such a union are affected (no father-toson transmission); (6) in the rare event of the union of an affected male and a heterozygous female, half of the daughters are homozygous affected and half are heterozygous carriers; while half of the sons are hemizygous affected (maternal inheritance) and half are normal; (7) if the trait is rare, parents and relatives are normal except for male relatives in the female line (e.g., on average, half of maternal uncles are affected). This "uncle and nephew" pattern gives rise to an oblique pedigree pattern, in contrast to the horizontal pattern of autosomal recessive conditions and the vertical pattern of autosomal dominant conditions.

Duchenne muscular dystrophy (DMD) and the milder Becker muscular dystrophy (BMD) are the product of mutations in the dystrophin gene on the X chromosome. The most distinctive feature of Duchenne muscular dystrophy is a progressive proximal muscular dystrophy with characteristic pseudohypertrophy of the calves. On average, a typical patient with DMD is diagnosed around the age of five, is wheelchair dependent at twelve years of age, and is dead before the age of twenty. One-third of cases represent new mutations.

Polygenic Traits and Multifactorial Genetic Diseases

Most phenotypic traits are determined by many genes collaborating at different loci (polygenic) rather than by single gene effects. Parents and offspring, and usually siblings, have 50 percent of their genes in common. Second-degree relatives share, on average, one-fourth of all genes, and third-degree relatives (cousins) share one-eighth. As the degree of relation becomes more distant, the probability of inheriting the same combination of genes is reduced, and the degree of resemblance is likely to be less.

Many common chronic diseases (e.g., essential hypertension, coronary artery disease, and schizophrenia) and the common birth defects of children (e.g., cleft palate, cleft lip, and neural tube defects) that tend to run in families fit best into the category of multifactorial genetic diseases. Multifactorial genetic diseases have both a polygenic component and an environmental component of causative factors. Susceptibility, or risk, genes are present in low frequency in the population at large. However, if any one individual has a particularly large number of such genes, the disease may manifest. When an individual is unfortunate enough to have inherited just the right (or wrong) combination of risk genes, he or she passes beyond a "risk threshold" at which environmental factors may determine the expression and severity of disease. In order for another family member to develop the same disease, that individual would have to inherit the same, or a very similar, combination of genes. The likelihood of such an occurrence is clearly greater in first-degree than in more distant relatives. The chances of another relative inheriting the right combination of risk genes decreases as the number of genes required to express a given trait increases. For example, the recurrence risk for siblings in neural tube defects is almost 4 percent, or ten times greater than the risk in the population as a whole.

Chromosomal Disorders

Failure of appropriate segregation (nondisjunction) during meiosis by allelic chromosomes or by sister chromatids can lead to an imbalance in the number of chromosomes present in a gamete. The frequency of chromosomal nondisjunction increases with increasing maternal age, with up to 1 percent of the offspring of mothers aged thirty-five and 10 percent of the offspring of mothers aged forty-five or older exhibiting such abnormalities. A zygote with only one copy (monosomy) of any one autosome is nonviable, and three (trisomy) or more copies of any one type of autosomal chromosome are also typically lethal. Exceptions do occur, the most common of which is trisomy 21, or Down syndrome.

Due to lyonization, nondisjunction of the X chromosome is better tolerated. XO individuals (Turner's syndrome) are phenotypically female, but are typically sterile. The Y chromosome is dominant, hence XXY individuals (Klinefelter's syndrome) are phenotypically male. However, affected men are also commonly sterile. Rare individuals with apparent Klinefelter's syndrome have been fertile, but these individuals are typically mosaics, with a sufficient population of chromosomally normal cells to yield viable gametes.

(SEE ALSO: Congenital Anomalies; Genes; Genetics and Health; Human Genome Project; Medical Genetics)

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— HARRY W. SCHROEDER, JR.

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