A monogenic or mendelian disorder is caused by a mutation or alteration in a single locus or gene in one or both members of a gene pair. Types of mendelian inheritance include autosomal dominant, autosomal recessive, X-linked, and Y-linked. Other monogenic inheritance patterns, described subsequently, include mitochondrial inheritance, uniparental disomy, imprinting, and trinucleotide repeat expansion-also termed anticipation. By age 25, approximately 0.4 percent of the population exhibits an abnormality attributed to a monogenic disorder, and 2 percent will have at least one such disorder during their lifetime (Table 13-3).
When considering inheritance, it is the phenotype that is dominant or recessive, not the genotype. With a dominant disease, the normal gene may direct the production of normal protein, but the phenotype is abnormal because it is determined by protein produced by the abnormal gene. With a recessive disease, a heterozygous carrier may produce detectable levels of an abnormal gene product but have no features of the condition because the phenotype is directed by the product of the normal co-gene. For example, erythrocytes from carriers of sickle-cell anemia contain approximately 30 percent hemoglobin S, but because the other 70 percent is hemoglobin A, these cells do not usually sickle in vitro.
Genetic heterogeneiy explains how diferent genetic mechanisms can result in the same phenotype. Locus heterogeneiy indicates
TABLE 13-3. Selected Monogenic (Mendelian) Disorders that a speciic disease phenotype can be caused by mutations in diferent genetic loci. It also explains why some diseases appear to follow more than one type of inheritance. An example is retinitis pigmentosa, which may develop following mutations in at least 35 diferent genes or loci and may result in autosomal dominant, autosomal recessive, or X-linked forms.
Alelic heterogeneiy describes how diferent mutations of the same gene may afect presentation of a particular disease. For example, although only one gene has been associated with cystic ibrosis-the cystic ibrosis conductance transmembrane regulator gene-more than 2000 mutations in this gene have been described and result in variable disease severity (Chaps. 14 and 51, pp. 289 and 997).
can arise from diferent mutations in the same gene. As an example, mutations in the ibroblast growth actor receptor 3 (FGF3) gene may result in several diferent skeletal disorders, including achondroplasia and thanatophoric dysplasia, both of which are discussed in Chapter 10 (p. 210).
If only one copy of a gene pair determines the phenotype, that gene is considered to be dominant. Carriers have a 50-percent chance of passing on the afected gene with each conception. A gene with a dominant mutation generally speciies the phenotype in preference to the normal gene. That said, not all individuals will necessarily manifest an autosomal dominant condition the same way. Factors that afect the phenotype of an autosomal dominant condition include penetrance, expressivity, and occasionally, presence of codominant genes.
his characteristic describes whether or not a dominant gene is expressed at all. A gene with recognizable phenotypic expression in all individuals is 100-percent penetrant, whereas penetrance is incomplete if some carriers express the gene but some do not. his may be quantitatively expressed-for example, a gene that is expressed in some way in 80 percent of individuals who have that gene is 80-percent penetrant. Importantly, incomplete penetrance explains why some autosomal dominant diseases may appear to "skip" generations.
Individuals with the same autosomal dominant trait may manifest the condition diferently, even within the same family. Genes with variable expressivity can produce disease manifestations that range from mild to severe. Examples include neuroibromatosis, tuberous sclerosis, and adult polycystic kidney disease.