Genetic heterogeneity is most commonly due to the presence of multiple alleles at a single locus, a situation referred to as allelic heterogeneity (see Chapter 7 and Table 11-1). In many instances, there is a clear genotype-phenotype correlation between a specific allele and a specific phenotype. The most common explanation for the effect of allelic heterogeneity on the clinical phenotype is that alleles that confer more residual function on the mutant protein are often associated with a milder form of the principal phenotype associated with the disease. In some instances, however, alleles that confer some residual protein function are associated with only one or a subset of the complete set of phenotypes seen with a missing or completely nonfunctional allele (frequently termed a null allele). As we will explore more fully in Chapter 12, this situation prevails with certain variants of the cystic fibrosis gene, CFTR; these variants lead to a phenotypically different condition, congenital absence of the vas deferens, but not to the other manifestations of cystic fibrosis.
A second explanation for allele-based variation in phenotype is that the variation may reflect the specific property of the protein that is most perturbed by the mutation. This situation is well illustrated by Hb Kempsey, a β-globin allele that maintains the hemoglobin in a high oxygen affinity structure, causing polycythemia because the reduced peripheral delivery of oxygen is misinterpreted by the hematopoietic system as being due to an inadequate production of red blood cells.
The biochemical and clinical consequences of a specific mutation in a protein are often unpredictable. Thus no one would have foreseen that the β-globin allele associated with sickle cell disease would lead to the formation of globin polymers that deform erythrocytes to a sickle cell shape (see later in this chapter). Sickle cell disease is highly unusual in that it results only from a single specific mutation—the Glu6Val substitution in the β-globin chain—whereas most disease phenotypes can arise from any of a number or many substitutions, usually loss-of-function mutations, in the affected protein.