Disorders with Multifactorial Inheritance

As pointed out earlier, the multifactorial disorders result from the combined actions of environmental influences and two or more mutant genes having additive effects. The genetic

component exerts a dosage effect—the greater the number of inherited deleterious genes, the more severe the expression of the disease. Because environmental factors significantly influence

the expression of these genetic disorders, the term polygenic inheritance should not be used.

A number of normal phenotypic characteristics are governed by multifactorial inheritance, such as hair color, eye color, skin color, height, and intelligence. These characteristics exhibit a

continuous variation in population groups, producing the standard bell-shaped curve of distribution. Environmental influences, however, significantly modify the phenotypic expression of

multifactorial traits. For example, type II diabetes mellitus has many of the features of a multifactorial disorder. It is well recognized clinically that individuals often first manifest this disease

after weight gain. Thus, obesity as well as other environmental influences unmasks the diabetic genetic trait. Nutritional influences may cause even monozygous twins to achieve different

heights. The culturally deprived child cannot achieve his or her full intellectual capacity.

The following features characterize multifactorial inheritance. These have been established for the multifactorial inheritance of congenital malformations and, in all likelihood, obtain for

other multifactorial diseases.[44]

• The risk of expressing a multifactorial disorder is conditioned by the number of mutant genes inherited. Thus, the risk is greater in siblings of patients having severe expressions of

the disorder. For example, the risk of cleft lip in the siblings of an index case is 2.5% if the cleft lip is unilateral but 6% if it is bilateral. Similarly, the greater the number of affected

relatives, the higher is the risk for other relatives.

• The rate of recurrence of the disorder (in the range of 2% to 7%) is the same for all first-degree relatives (i.e., parents, siblings, and offspring) of the affected individual. Thus, if

parents have had one affected child, the risk that the next child will be affected is between 2% and 7%. Similarly, there is the same chance that one of the parents will be affected.

• The likelihood that both identical twins will be affected is significantly less than 100% but is much greater than the chance that both nonidentical twins will be affected. Experience

has proven, for example, that the frequency of concordance for identical twins is in the range of 20% to 40%.

• The risk of recurrence of the phenotypic abnormality in subsequent pregnancies depends on the outcome in previous pregnancies. When one child is affected, there is up to a 7%

chance that the next child will be affected, but after two affected siblings, the risk rises to about 9%.

• Expression of a multifactorial trait may be continuous (lack a distinct phenotype, e.g., height) or discontinuous (with a distinct phenotype, e.g., diabetes mellitus). In the latter,

disease is expressed only when the combined influences of the genes and environment cross a certain threshold. In the case of diabetes, for example, the risk of phenotypic expression

increases when the blood glucose levels go above a certain level.

Assigning a disease to this mode of inheritance must be done with caution. It depends on many factors but first on familial clustering and the exclusion of mendelian and chromosomal modes

of transmission. A range of levels of severity of a disease is suggestive of multifactorial inheritance, but, as pointed out earlier, variable expressivity and reduced penetrance of single mutant

genes may also account for this

TABLE 5-8-- Multifactorial Disorders

Disorder Chapter

Cleft lip or cleft palate (or both) Chapter 10

Congenital heart disease Chapter 12

Coronary heart disease Chapter 12

Hypertension Chapter 11

Gout Chapter 27

Diabetes mellitus Chapter 24

Pyloric stenosis Chapter 17

phenomenon. Because of these problems, sometimes it is difficult to distinguish between mendelian and multifactorial inheritance.

In contrast to the mendelian disorders, many of which are uncommon, the multifactorial group includes some of the most common ailments to which humans are heir ( Table 5-8 ). Most of

these disorders are described in appropriate chapters elsewhere in this book.

Normal Karyotype

As is well known, human somatic cells contain 46 chromosomes; these comprise 22 homologous pairs of autosomes and two sex chromosomes, XX in the female and XY in the male. The

study of chromosomes—karyotyping—is the basic tool of the cytogeneticist. The usual procedure of producing a chromosome spread is to arrest mitosis in dividing cells in metaphase by the

use of mitotic spindle inhibitors (e.g., colcemid) and then to stain the chromosomes. In a metaphase spread, the individual chromosomes take the form of two chromatids connected at the

centromere. A karyotype is a standard arrangement of a photographed or imaged stained metaphase spread in which chromosome pairs are arranged in order of decreasing length.

A variety of staining methods that allow identification of each individual chromosome on the basis of a distinctive and reliable pattern of alternating light and dark bands along the length of

the chromosome have been developed. The one most commonly employed uses a Giemsa stain and is hence called G banding. A normal male karyotype with G banding is illustrated in

Figure 5-20 . With G banding, approximately 400 to 800 bands per haploid set can be detected. The resolution obtained by banding techniques can be dramatically improved by obtaining the

cells in prophase. The individual chromosomes appear markedly elongated, and up to 1500 bands per karyotype may be recognized. The use of these banding techniques permits certain

identification of each chromosome as well as delineation of precise breakpoints and other subtle alterations, to be described later.

Before this discussion of the normal karyotype is concluded, reference must be made to commonly used cytogenetic terminology. Karyotypes are usually described using a shorthand system

of notations. The following order is used: Total number of chromosomes is given first, followed by the sex chromosome complement, and finally the description of abnormalities in ascending

numerical order. For example, a

Figure 5-20Normal male karyotype with G banding. (Courtesy of Dr. Nancy Schneider, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)

Figure 5-21Details of banding pattern of the X chromosome (also called "idiogram"). Note the nomenclature of arms, regions, bands, and sub-bands. On the right side, the approximate

locations of some genes that cause disease are indicated.

Figure 5-22Fluorescence in situ hybridization (FISH). Interphase nuclei of a childhood hepatic cancer (hepatoblastoma) stained with a fluorescent DNA probe that hybridizes to

chromosome 20. Under ultraviolet light, each nucleus reveals three bright yellow fluorescent dots, representing three copies of chromosome 20. Normal diploid cells (not shown) have two

fluorescent dots. (Courtesy of Dr. Vijay Tonk, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)

Figure 5-23FISH. A metaphase spread in which two fluorescent probes, one for the terminal ends of chromosome 22 and the other for the D22S75 locus, which maps to chromosome 22,

have been used. The terminal ends of the two chromosomes 22 have been labeled. One of the two chromosomes does not stain with the probe for the D22S75 locus, indicating a

microdeletion in this region. This deletion gives rise to the 22q11.2 deletion syndrome. (Courtesy of Dr. Nancy Schneider, Department of Pathology, University of Texas Southwestern

Medical Center, Dallas, TX.)

Figure 5-24Chromosome painting with a library of chromosome 22-specific DNA probes. The presence of three fluorescent chromosomes indicates that the patient has trisomy 22.

(Courtesy of Dr. Charleen M. Moore, The University of Texas Health Science Center at San Antonio, TX.)

Figure 5-25Spectral karyotype. (Courtesy of Dr. Janet D. Rowley, University of Chicago Pritzker Medical School, Chicago, IL.)

Figure 5-26Types of chromosomal rearrangements.

Figure 5-27 G banded karyotype of a male with trisomy 21. (Courtesy of Dr. Nancy Schneider, University of Texas Southwestern Medical Center, Dallas, TX.)

Figure 5-33 A model for the action of familial mental retardation protein (FMRP) in neurons. (Adapted from Hin P, Warren ST: New insights into fragile-X syndrome: from molecules to

neurobehavior. Trends Biochem Sci 28:152, 2003.)

TABLE 5-9-- Summary of Trinucleotide Repeat Disorders

Date: 2016-04-22; view: 661