Categories Of Genetic Disorders

Currently, there is an enormous amount of information with respect to numbers of and characteristics of various genetic

Fig. 1. A human male karyotype (G-banded) showing the 22 pairs of autosomes and the 2 sex chromosomes (XY).

Table 1

Types of Noncoding "Junk" DNA Sequence

Intron DNA sequences that interrupt the coding (exon) sequences of a gene

Satellite Short repetitive DNA sequences that occur at the ends (telomeres) and centers (centromeres) of a chromosome

Minisatellite Repetitive sequences that are shorter than satellites and found throughout the genome (variable numbers of tandem repeats)

Microsatellite Even shorter repetitive sequences: dinucleotides, trinuceotides, and tetranucleotides (short tandem repeats)

3'-Untranslated regions DNA that is transcribed into RNA at the end of a gene but is not translated into protein; function in regulation of gene expression

Short interspersed elements (SINEs) Well represented by the 300-bp Alu repeat that occurs approx 500,000 times within the genome

Long interspersed elements (LINEs) Up to 700 bp in length and scattered throughout the genome diseases and syndromes. To this list are added the growing numbers of diseases for which genetic mechanisms of disease are being identified almost daily. Genetic diseases can be categorized into three major groups: (1) chromosomal disorders, (2) monogenic or single-gene disorders, and (3) polygenic or multifactorial disorders.

Chromosomal disorders are the result of the loss, gain, or abnormal arrangement of one or more chromosomes, which results in excessive or deficient amounts of genetic material. Syndromes characterized by multiple birth defects and various forms of hematopoietic malignancy are examples of chromosomal disorders. An individual's karyotype (number and structure of chromosomes) contains 46 chromosomes; 44 of these are autosomes, designated by number from 1 to 22, and 2 are sex chromosomes designated X and Y (Fig. 1). The individual chromosomes can be distinguished from one another by size, location of centromere, and unique banding patterns after special staining methods. Chromosomal alterations usually involve large segments of DNA containing numerous genes and can be classified into four groups:

1. Aneuploidy, referring to an excess or loss of one or more chromosomes

2. Deletion, resulting from breakage and/or loss of a portion of a chromosome

3. Translocation, referring to breakage of two chromosomes with exchange of the broken parts between the chromosomes

4. Isochromosome formation, resulting from splitting of a chromosome at the centromere during mitosis, such that one arm is lost and the other duplicated to form one chromosome with identical arms

Monogenic disorders are the result of a single mutant gene and display traditional Mendelian inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked. The overall population frequency of monogenic disorders is

Fig. 2. (A) Schematic representation of chromosome locus and allele designation; (B) differentiation of a genetic locus from homozygous and heterozygous genetic alleles.

thought to be approx 10 per 1000 live births. The Human Genome Project has enabled the discovery of increasing numbers of disease-associated genes; molecular genetic testing is becoming more routine because this information is combined with advances in molecular diagnostic technologies. Biochemical lesions characteristic of monogenic disorders result from defects in a wide array of proteins, many of which are not yet characterized.

Polygenic or multifactorial disorders consist of chronic diseases of adulthood, congenital malformations, and dysmorphic syndromes. These disorders result from multiple genetic and/or epigenetic factors that do not conform to traditional Mendelian inheritance patterns. Diseases such as hypertension, ischemic heart disease, Alzheimer's disease, diabetes mellitus, and cancer develop from the interaction of numerous altered genes and environmental factors. The molecular dissection of the genetic complexity of most polygenic disorders is only in its infancy.

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