Key molecular concepts that can account for differences in the observed clinical phenotype associated with a genetic disease are:

• Allelic heterogeneity

• Locus heterogeneity

• Effect of modifier genes

Each of these concepts is illustrated by variants in the α- globin and/ or β- globin genes (Table 1).

Table1. Types of Heterogeneity Associated With Genetic Disease

Allelic Heterogeneity

Genetic heterogeneity is most commonly due to the presence of multiple alleles at a single locus, a situation referred to as allelic heterogeneity (see Table 2). In some instances there may be 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 altered 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 functions are associated with only one or a subset of the phenotypes seen with a missing or completely nonfunctional allele (frequently termed a null allele). As we will explore more fully in Chapter 13, this situation prevails with certain variants of the cystic fibro sis gene, CFTR, that lead to a phenotypically different condition—congenital absence of the vas deferens, but not to the other manifestations of cystic fibrosis. An important exception to this rule relates to variants that act in a dominant- negative fashion, as exemplified by select mis sense variants in the genes encoding components of type I collagen that result in a more severe form of osteogenesis imperfecta than with a null allele.

Table2. Eight Steps at Which DNA Variants Can Disrupt the Production of a Normal Protein

A second explanation for allele- based differences in phenotype is that a specific property of the protein may be more perturbed by a particular variant. This situation is well illustrated by Hb Kempsey, a β- globin allele that maintains the hemoglobin in a high oxygen affinity structure. This causes 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 consequences of a specific variant on the function of a protein can be unpredictable. 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). However, sickle cell disease is also unusual in that it results only from a single specific variant— the p.Glu6Val substitution in the β- globin chain— whereas most genetic diseases can arise from any of a number of different DNA- level variants in the corresponding gene.

Locus Heterogeneity

 Genetic heterogeneity also arises when variants at more than one locus can result in a specific clinical condition—a situation termed locus heterogeneity. This phenomenon is illustrated by the finding that thalassemia can result from variants in either the α- globin or β- globin chain genes (see Table 1). Once locus heterogeneity has been documented, careful comparison of the phenotype associated with each gene sometimes reveals that the phenotype is not as homogeneous as initially believed.

Modifier Genes

Sometimes even the most robust genotype- phenotype relationships are found not to hold for a specific individual. Such phenotypic variation can, in principle, be ascribed to nongenetic (e.g., environmental, stochastic) factors or to the action of other genes, termed modifier genes. Identified modifier genes for specific human monogenic disorders are growing in number; however, there remain relatively few examples with clinically relevant effect sizes or therapeutic significance. As described later in this chapter, individuals with β- thalassemia who also have a deletion at the α- globin locus can have a less severe phenotype.

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