ABSTRACT
There are several potential causes of variable phenotypes and reduced penetrance of autosomal dominant traits. These include alternative alleles (allelic heterogeneity), alternative loci (locus heterogeneity), modifier genes, and environmental factors. An example of a genetic modifier in humans is the decreased amount of sickle hemoglobin that is seen in patients with sickle trait who also are heterozygous for alpha thalassemia trait.101,102 The lower sickle hemoglobin is caused by the globin not competing as well as the B globin for the limited globin molecules required to form a2B2 heterotetramers. Genetic modifiers can affect penetrance, expressivity, and pleiotropy. Depending on the nature of the phenotypic effect, modifiers might cause more or less extreme, novel or normal phenotypes. Modifier genes discovered in experimental species, such as mice, are often relevant to human diseases and genetic linkages discovered in other species can guide the search for linkage in humans.102,103
Studies of the estrogen-response elements in the BMPR2 promoter are needed to determine if they contribute to the penetrance of, as well as the female preponderance that is seen in FPPH. Second, promoters in the normal BMPR2 allele may subtlely affect its expression and thus may alter effects of the mutant BMPR2 product.104 Third, variations in modifier genes that are encoded in the nuclear or mitochondrial chromosomes may affect the penetrance of FPPH.104
