The characteristics of autosomal dominant inheritance in humans can be summarized as follows: (1) There is a vertical pattern in the pedigree, with multiple generations affected (eFigure 40–3). (2) Heterozygotes for the mutant allele show an abnormal phenotype. (3) Males and females are affected with equal frequency and severity. (4) Only one parent must be affected for an offspring to be at risk for developing the phenotype. (5) When an affected person mates with an unaffected one, each offspring has a 50% chance of inheriting the affected phenotype. This is true regardless of the sex of the affected parent—specifically, male-to-male can transmission occur. (6) The frequency of sporadic cases is positively associated with the severity of the phenotype. More precisely, the greater the reproductive fitness of affected persons, the less likely it is that any given case resulted from a new mutation. (7) The average age of fathers is advanced for isolated (sporadic or new mutation) cases.
A pedigree illustrating autosomal dominant inheritance. Square symbols indicate males and circles females; open symbols indicate that the person is phenotypically unaffected, and filled symbols indicate that the phenotype is present to some extent.
Autosomal dominant phenotypes are often age-dependent, less severe than autosomal recessive ones, and associated with malformations or other physical features. They are pleiotropic in that multiple, even seemingly unrelated clinical manifestations derive from the same mutation, and variable in that expression of the same mutation among people will differ.
Penetrance is a concept associated with mendelian conditions—especially dominant ones—and the term is often misused. It should be defined as an expression of the frequency of appearance of a phenotype (dominant or recessive) when one or more mutant alleles are present. For individuals, penetrance is an all-or-none phenomenon—the phenotype is either present (penetrant) or not (nonpenetrant). The term variability—not "incomplete penetrance"—should be used to denote differences in expression of an allele.
The most frequent cause of apparent nonpenetrance is insensitivity of the methods for detecting the phenotype. If an apparently normal parent of a child with a dominant condition was in fact heterozygous for the mutation, the parent would have a 50% chance at each subsequent conception of having another affected child. A common cause of nonpenetrance in adult-onset mendelian diseases is death of the affected person before the phenotype becomes evident but after transmission of the mutant allele to offspring. Thus, accurate genetic counseling demands careful attention to the family medical history and high-resolution scrutiny of both parents of a child with a condition known to be a mendelian dominant trait.
When both alleles are expressed in the heterozygote, as in blood group AB, in sickle trait (HbS/HbA), in the major histocompatibility antigens (eg, A2B5/A3B17), or in sickle-C disease (HbS/HbC), the phenotype is called codominant.
In human dominant phenotypes, the mutant allele in homozygotes is almost always more severe than in heterozygotes.