Abnormalities of Chromosome Number.

A euploid cell is a cell with the correct or normal number of chromosomes within the cell. Because most gametes are haploid (1N, 23 chromosomes) and most somatic cells are diploid (2N, 46 chromosomes), they are both considered euploid cells. Deviations from the correct number of chromosomes per cell can be one of two types: (1) polyploidy, in which the deviation is an exact multiple of the haploid number of chromosomes or one chromosome set (23 chromosomes); or (2) aneuploidy, in which the numeric deviation is not an exact multiple of the haploid set. A triploid (3N) cell is an example of a polyploidy. It has 69 chromosomes. A tetraploid (4N) cell, also an example of a polyploidy, has 92 chromosomes.

Aneuploidy is the most commonly identified chromosome abnormality in humans and the leading genetic cause of intellectual disability. A monosomy is the product of the union between a normal gamete and a gamete that is missing a chromosome. Monosomic individuals have only 45 chromosomes in each of their cells. The product of the union of a normal gamete with a gamete containing an extra chromosome is a trisomy. The most common autosomal aneuploid conditions involve trisomies. Trisomic individuals have 47 chromosomes in most or all of their cells.

The vast majority of trisomies occur during oogenesis (the process by which a premeiotic female germ cell divides into a mature egg); the incidence of these types of chromosomal errors increases exponentially with advancing maternal age. Although variation exists among trisomies with regard to the parent and stage of origin of the extra chromosome, most trisomies are maternal meiosis I (MI) errors. This means that most trisomies are caused by nondisjunction during the first meiotic division. The first meiotic division involves the segregation of homologous or similar chromosomes. One pair of chromosomes fails to separate. One resulting cell contains both chromosomes, and the other contains none. The fact that most trisomies are maternal MI errors is not that surprising, because maternal MI occurs over a long time span. It is initiated in precursor cells during fetal development, but it is not completed until the time those cells undergo ovulation after menarche.

The most common trisomy abnormality is Down syndrome (DS). Approximately one in every 691 newborns has DS; there are over 400,000 individuals with DS living in the United States (www.ndss.org). Ninety-five percent of individuals with DS have trisomy 21 (nondisjunction) or an extra chromosome 21 (47,XX+21, female with DS; or 47,XY+21, male with DS). Another type of DS, translocation, occurs when extra chromosome 21 material is present in every cell of the individual but it is attached to another chromosome. In the third type of DS, mosaicism, extra chromosome 21 material is found in some but not all of the cells.

Although the risk for having a child with DS increases with maternal age (incidence is approximately 1 in 1200 for a 25-year-old woman; 1 in 350 for a 35-year-old woman; and 1 in 30 for a 45-year-old woman), children with Down syndrome can be born to mothers of any age (www.ndss.org). Eighty percent of children with Down syndrome are born to mothers younger than 35 years. The risk for a mother having a second child with Down syndrome is about 1% when the cause of the Down syndrome is trisomy 21.

Other autosomal trisomies that maternity nurses might see are trisomy 18 (Edwards syndrome) and trisomy 13 (Patau syndrome). Trisomy 18 is more common than trisomy 13; it occurs in about 1 of 3000 live births versus 1 of 10,000 live births for trisomy 13. Infants with trisomy 18 and trisomy 13 usually have severe to profound intellectual disabilities. Although both conditions have a poor prognosis, with the vast majority of affected infants dying before they reach their first birthday, a growing number of infants with these trisomies are living longer and a small number are actually living into their 40s and 50s.

Nondisjunction can also occur during mitosis. If this occurs early in development, when cell lines are forming, the individual has a mixture of cells, some with a normal number of chromosomes and others either missing a chromosome or containing an extra chromosome. This condition is known as mosaicism. The most common form of mosaicism in autosomes is mosaic Down syndrome.

Abnormalities of Chromosome Structure.

Structural abnormalities can occur in any chromosome. Types of structural abnormalities include translocation, duplication, deletion, microdeletion, and inversion. Translocation results when there is an exchange of chromosomal material between two chromosomes. Exposure to certain drugs, viruses, and radiation can cause translocations, but often they arise for no apparent reason.

The two major types of translocation are reciprocal and robertsonian. Reciprocal translocations are the most common. In a reciprocal translocation, either the parts of the two chromosomes are exchanged equally (balanced translocation) or a part of a chromosome is transferred to a different chromosome, creating an unbalanced translocation because there is extra chromosomal material—extra of one chromosome but correct amount or deficient amount of the other chromosome. In a balanced translocation, the individual is phenotypically normal because there is no extra chromosome material; it is just rearranged. In an unbalanced translocation, the individual will be both genotypically and phenotypically abnormal.

In a robertsonian translocation, the short arms (p arms) of two different acrocentric chromosomes (chromosomes with very short p arms) break, leaving sticky ends that then cause the two long arms (q arms) to stick together. This forms a new, large chromosome that is made of the two long arms. The individual with a balanced robertsonian translocation has 45 chromosomes. Because the short arm of acrocentric chromosomes contains genes for ribosomal RNA and these genes are represented elsewhere, the individual usually does not show any symptoms. The individual may produce an unbalanced gamete (sperm or egg with too many or two few genes). This can lead to reproductive difficulties such as miscarriages or birth defects.

In duplication, there is an extra chromosomal segment within the same homologous or another nonhomologous chromosome. Clinical findings are highly variable and depend on which of the chromosomal segments are involved.

Deletions result in the loss of chromosomal material and partial monosomy for the chromosome involved. Microdeletions are deletions too small to be detected by standard cytogenetic techniques. Whenever a portion of a chromosome is deleted from one chromosome and added to another, the gamete produced may have either extra copies of genes or too few copies. The clinical effects produced may be mild or severe depending on the amount of genetic material involved. Two of the more common conditions are the deletion of the short arm of chromosome 5 (cri du chat syndrome) and the deletion of the long arm of chromosome 18.

Inversions are deviations in which a portion of the chromosome has been rearranged in reverse order. Few birth defects have been attributed to the presence of inversions, but it is suspected that inversions may be responsible for problems with infertility and miscarriages. More than 40% of inversions involve chromosome 9.

Autosomal Dominant Inheritance.

Autosomal dominant inheritance disorders are those in which only one copy of a variant allele is needed for phenotypic expression. The variant allele may be a result of a mutation—a spontaneous and permanent change in the normal gene structure in which case the disorder occurs for the first time in the family. Usually an affected individual comes from multiple generations having the disorder. An affected parent who is heterozygous for the trait has a 50% chance of passing the variant allele to each offspring (see Fig. 6-2, B and C). There is a vertical pattern of inheritance (i.e., there is no skipping of generations; if an individual has an autosomal dominant disorder such as HD, so must one of his or her parents). Males and females are equally affected.

Autosomal dominant disorders are not always expressed with the same severity of symptoms. For example, a woman who has an autosomal dominant disorder may show few symptoms and may not become aware of her diagnosis until after she gives birth to a severely affected child. Predicting whether an offspring will have a minor or severe abnormality is not possible. Examples of autosomal dominant disorders are HD, Marfan syndrome, neurofibromatosis, myotonic dystrophy, Stickler syndrome, Treacher Collins syndrome, and achondroplasia (dwarfism).

Autosomal Recessive Inheritance.

Autosomal recessive inheritance disorders are those in which both genes of a pair associated with the disorder must be abnormal for the disorder to be expressed. Heterozygous individuals have only one variant allele and are unaffected clinically because their normal gene overshadows the variant allele. They are known as carriers of the recessive trait. Because these recessive traits are inherited by generations of the same family, an increased incidence of the disorder occurs in consanguineous matings (closely related parents). For the trait to be expressed, two carriers must each contribute a variant allele to the offspring (see Fig. 6-2, C). The chance of the trait occurring in each child is 25%. A clinically normal offspring may be a carrier of the gene. Autosomal recessive disorders have a horizontal pattern of inheritance rather than the vertical pattern seen with autosomal dominant disorders. That is, autosomal recessive disorders are usually observed in one or more siblings but not in earlier generations. Males and females are equally affected. Most inborn errors of metabolism (IEMs), such as phenylketonuria, galactosemia, maple syrup urine disease, Tay-Sachs disease, sickle cell anemia, and cystic fibrosis, are autosomal recessive inherited disorders.

Inborn Errors of Metabolism.

More than 350 inborn errors of metabolism have been recognized (Jorde, Carey, and Bamshad, 2010). Individually, IEMs are relatively rare, but collectively, they are common (1 in 5000 live births). Most IEMs are inherited in an autosomal recessive pattern. IEMs occur when a gene mutation reduces the efficiency of encoded enzymes to a level at which normal metabolism cannot occur. Defective enzyme action interrupts the normal series of chemical reactions from the affected point onward. The result may be an accumulation of a damaging product, such as phenylalanine in PKU, or the absence of a necessary product, such as the lack of melanin in albinism caused by lack of tyrosinase. Diagnostic and carrier testing is available for a growing number of IEMs. In addition, many states in the United States have started screening for specific IEMs as part of their expanded newborn screening programs using tandem mass spectrometry. However, many of the deaths caused by IEMs are the result of enzyme variants not currently screened for in many of the newborn screening programs (Jorde, Carey, and Bamshad, 2010). (See discussion of IEMs in Chapter 25.)

X-Linked Dominant Inheritance.

X-linked dominant inheritance disorders occur in males and heterozygous females, but because of X inactivation, affected females are usually less severely affected than affected males and they are more likely to transmit the variant allele to their offspring. Heterozygous females (females who have one wild-type allele and one variant allele) have a 50% chance of transmitting the variant allele to each offspring. The variant allele is often lethal in affected males since, unlike affected females, they have no normal gene (wild-type allele). Mating of an affected male and an unaffected female is uncommon as a result of the tendency for the variant allele to be lethal in affected males. Relatively few X-linked dominant disorders have been identified. Two examples are vitamin D–resistant rickets and Rett syndrome.

X-Linked Recessive Inheritance.

Abnormal genes for X-linked recessive inheritance disorders are carried on the X chromosome. Females may be heterozygous or homozygous for traits carried on the X chromosome because they have two X chromosomes. Males are hemizygous because they have only one X chromosome, which carries genes with no alleles on the Y chromosome. Therefore X-linked recessive disorders are most commonly manifested in the male with the abnormal gene on his single X chromosome. Hemophilia, color blindness, and Duchenne muscular dystrophy are X-linked recessive disorders.

The male with an X-linked recessive disorder receives the disease-associated allele from his carrier mother on her affected X chromosome. Female carriers (those heterozygous for the trait) have a 50% probability of transmitting the disease-associated allele to each offspring. An affected male can pass the disease-associated allele to his daughters but not to his sons. The daughters will be carriers of the trait if they receive a normal gene on the X chromosome from their mother. They will be affected only if they receive a disease-associated allele on the X chromosome from both their mother and their father.