Genes in Families

Genes in Families

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.

1 Mendel's first law stated that—from the perspective of the phenotype—it mattered not from which parent a particular mutant allele was inherited. For years this principle was thought to be too obvious to be codified as anybody's "law" and was therefore ignored. In fact, however, recent evidence from studies of human disorders suggests that certain genes are "processed" (imprinted) as they move through the gonad and that processing in the testis is different from that in the ovary. Thus, not only is this first mendelian principle important, it was incorrect as originally formulated from observations in peas.

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

Autosomal Dominant Inheritance

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 (Figure 44–3). (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 transmission occurs. (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.

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