When a person has a pair of identical alleles at a locus encoded in nuclear DNA, he or she is said to be homozygous, or a homozygote; when the alleles are different and one of the alleles is the wild-type allele, he or she is heterozygous, or a heterozygote. The term compound heterozygote is used to describe a genotype in which two different mutant alleles of a gene are present, rather than one wild-type and one mutant allele. These terms (homozygous, heterozygous, and compound heterozygous) can be applied either to a person or to a genotype. In the special case in which a male has an abnormal allele for a gene located on the X chromosome and there is no other copy of the gene, he is neither homozygous nor heterozygous but is referred to as hemizygous. Mitochondrial DNA is still another special case. In contrast to the two copies of each gene per diploid cell, mitochondrial DNA molecules, and the genes encoded by the mitochondrial genome, are present in tens to thousands of copies per cell (see Chapter 2). For this reason, the terms homozygous, heterozygous, and hemizygous are not used to describe genotypes at mitochondrial loci.
A single-gene disorder is one that is determined primarily by the alleles at a single locus. The known single-gene diseases are listed in the late Victor A. McKusick’s classic reference, Mendelian Inheritance in Man, which has been indispensable to medical geneticists for decades. These diseases follow one of the classic inheritance patterns in families (autosomal recessive, autosomal dominant, X-linked) and are therefore referred to as mendelian because, like the characteristics of the garden peas Gregor Mendel studied, they occur on average in fixed and predictable proportions among the offspring of specific types of matings.
A single abnormal gene or gene pair often produces multiple diverse phenotypic effects in multiple organ systems, with a variety of signs and symptoms occurring at different points during the life span. To cite just one example, individuals with a mutation in the VHL gene can have hemangioblastomas of the brain, spinal cord, and retina; renal cysts; pancreatic cysts; renal cell carcinoma; pheochromocytoma; and endolymphatic tumors of the inner ear; as well as tumors of the epididymis in males or of the broad ligament of the uterus in females—even though all of these disease manifestations stem from the same single mutation. Under these circumstances, the disorder is said to exhibit pleiotropy (from Greek pleion and tropos, more turns), and the expression of the gene defect is said to be pleiotropic. At present, for many pleiotropic disorders, the connection between the gene defect and the various manifestations is neither obvious nor well understood.
Single-gene disorders affect children disproportionately, but not exclusively. Serious single-gene disorders affect 1 in 300 neonates and are responsible for an estimated 7% of pediatric hospitalizations. Although less than 10% of single-gene disorders manifest after puberty, and only 1% occur after the end of the reproductive period, mendelian disorders are nonetheless important to consider in adult medicine. There are nearly 200 mendelian disorders whose phenotypes include common adult illnesses such as heart disease, stroke, cancer, and diabetes. Although mendelian disorders are by no means the major contributory factor in causing these common diseases in the population at large, they are important in individual patients because of their significance for the health of other family members and because of the availability of genetic testing and detailed management options for many of them.
Penetrance and Expressivity
For some genetic conditions, a disease-causing genotype is always fully expressed at birth as an abnormal phenotype. Clinical experience, however, teaches that other disorders are not expressed at all or may vary substantially in their signs and symptoms, clinical severity, or age of onset, even among members of a family who all share the same disease-causing genotype. Geneticists use distinct terms to describe such differences in clinical expression.
Penetrance is the probability that a mutant allele or alleles will have any phenotypic expression at all. When the frequency of expression of a phenotype is less than 100%—that is, when some of those who have the relevant genotype completely fail to express it—the disorder is said to show reduced or incomplete penetrance. Penetrance is all or nothing. It is the percentage of people at any given age with a predisposing genotype who are affected, regardless of the severity.
Penetrance of some disorders is age dependent; that is, it may occur any time, from early in intrauterine development all the way to the postreproductive years. Some disorders are lethal prenatally, whereas others can be recognized prenatally (e.g., by ultrasonography; see Chapter 17) but are consistent with a liveborn infant; still others may be recognized only at birth (congenital).* Other disorders have their onset typically or exclusively in childhood or in adulthood. Even in these, however, and sometimes even in the same family, two individuals carrying the same disease-causing genotype may develop the disease at very different ages.
In contrast to penetrance, expressivity refers not to the presence or absence of a phenotype, but to the severity of expression of that phenotype among individuals with the same disease-causing genotype. When the severity of disease differs in people who have the same genotype, the phenotype is said to show variable expressivity. Even in the same family, two individuals carrying the same mutant genes may have some signs and symptoms in common, whereas their other disease manifestations may be quite different, depending on which tissues or organs happen to be affected. The challenge to the clinician caring for these families is to not miss very subtle signs of a disorder in a family member and, as a result, either mistake mild expressivity for lack of penetrance or infer that the individual does not have the disease-causing genotype.