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Since the first decade of the twentieth century, the patterns of recurrence of specific human phenotypes have been explained in terms of principles first described by Mendel in the garden pea plant. Mendel’s second principle—usually referred to as his first1—is called the law of segregation and states that a pair of factors (alleles) that determines some trait separates (segregates) during formation of gametes. In simple terms, a heterozygous (A/a) person will produce two types of gametes with respect to this locus—one containing only A and one containing only a, in equal proportions. Offspring of this person will have a 50–50 chance of inheriting the A allele and a similar chance of inheriting the a allele.

The concepts of genes in individuals and in families can be combined to specify how mendelian traits will be inherited.


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 pathogenic variant. (7) The average age of fathers is advanced for isolated (sporadic or new pathogenic variant) cases.

eFigure 40–3

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 pathogenic variant, and variable in that expression of the same pathogenic variant 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 ...

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