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.
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 E2–3). (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.
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.
Autosomal Recessive Inheritance
The characteristics of autosomal recessive inheritance in humans can be summarized as follows: (1) A horizontal pattern occurs in the pedigree, with a single generation affected (Figure E2–4). (2) Males and females are affected with equal frequency and severity. (3) Inheritance is from both parents, each a heterozygote (carrier) and each usually clinically unaffected. (4) Each offspring of two carriers has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither mutant allele. Thus, two-thirds of all clinically unaffected offspring are carriers. (5) In matings between individuals, each with the same recessive phenotype, all offspring will be affected. (6) Affected individuals who mate with unaffected individuals who are not carriers have only unaffected offspring. (7) The rarer the recessive phenotype, the more likely it is that the parents are consanguineous (related).
A pedigree illustrating autosomal recessive inheritance. (Symbols as in Figure E2–3.)
Autosomal recessive phenotypes are often associated with deficient activity of enzymes and are thus termed inborn errors of metabolism. Such disorders include phenylketonuria, Tay-Sachs disease, and the various glycogen storage diseases and tend to be more severe, less variable, and less age-dependent than dominant conditions.
When an autosomal recessive condition is quite rare, the chance that the parents of affected offspring are consanguineous is increased. As a result, the prevalence of rare recessive conditions is high among inbred groups such as the Old Order Amish. On the other hand, when the autosomal recessive condition is common, the chance of consanguinity between parents of cases is no higher than in the general population.
Two different mutant alleles at the same locus, as in HbS/HbC, form a genetic compound (compound heterozygote). The phenotype usually lies between those produced by either allele present in the homozygous state. Because of the large number of mutations possible in a given gene, many autosomal recessive phenotypes are probably due to genetic compounds. Sickle cell disease is an exception. Consanguinity is strong presumptive evidence for true homozygosity of mutant alleles and against a genetic compound.
The general characteristics of X-linked inheritance in humans can be summarized as follows: (1) There is no male-to-male transmission of the phenotype (Figure E2–5). (2) Unaffected males do not transmit the phenotype. (3) All of the daughters of an affected male are heterozygous carriers. (4) Males are usually more severely affected than females. (5) Whether a heterozygous female is counted as affected—and whether the phenotype is called "recessive" or "dominant"—depends often on the sensitivity of the assay or examination. (6) Some mothers of affected males will not themselves be heterozygotes (ie, they will be homozygous normal) but will have a germinal mutation. The proportion of heterozygous (carrier) mothers is negatively associated with the severity of the condition. (7) Heterozygous women transmit the mutant gene to 50% of their sons, who are affected, and to 50% of their daughters, who are heterozygotes. (8) If an affected male mates with a heterozygous female, 50% of the male offspring will be affected, giving the false impression of male-to-male transmission. Of the female offspring of such matings, 50% will be affected as severely as the average hemizygous male; in small pedigrees, this pattern may simulate autosomal dominant inheritance.
A pedigree illustrating X-linked inheritance. (Symbols as in Figure E2–3.)
The characteristics of X-linked inheritance depend on phenotypic severity. For some disorders, affected males do not survive to reproduce. In such cases, about two-thirds of affected males have a carrier mother; in the remaining third, the disorder arises by new germinal mutation in an X chromosome of the mother. When the disorder is nearly always manifest in heterozygous females (X-linked dominant inheritance), females tend to be affected about twice as often as males; and on average an affected female transmits the phenotype to 50% of her sons and 50% of her daughters.
X-linked phenotypes are often clinically variable—particularly in heterozygous females—and suspected of being autosomal dominant with nonpenetrance. For example, Fabry disease (alpha-galactosidase A deficiency) may be clinically silent in carrier women or may cause stroke, kidney failure, or myocardial infarction by middle age.
Germinal mosaicism occurs in mothers of boys with X-linked conditions. The chance of such a mother having a second affected son or a heterozygous daughter depends on the fraction of her oocytes that carries the mutation. Currently, this fraction is impossible to determine. However, the presence of germinal mosaicism can be detected in some conditions (eg, Duchenne muscular dystrophy) in a family by analysis of DNA, and this knowledge becomes crucial for genetic counseling.
Mutations in the genes encoded by the mitochondrial chromosome cause a variety of diseases that affect (in particular) organs highly dependent on oxidative metabolism, such as the retina, brain, kidneys, and heart. Because a person's mitochondria derive almost entirely from the ovum, the inheritance pattern is distinct from that of mendelian disorders and is termed "maternal" or, more appropriately, "mitochondrial." An affected woman can pass the defective mitochondrial chromosome to all of her offspring, whereas an affected man has little risk of passing his mutation to a child (Figure E2–6). Because each cell and the ovum contain many mitochondria and because each mitochondrion contains many chromosomes, two situations are possible: If every chromosome in every mitochondrion carries the same mutation, the person is said to be homoplasmic for the mutation. On the other hand, if only some of the mitochondrial chromosomes carry the mutation, the person is heteroplasmic. In the latter case, an offspring may inherit relatively few mitochondria bearing the mutation and have mild disease or no disease.
Mitochondrial ("maternal") inheritance. A mitochondrial genetic mutation, indicated by darkened symbols, is passed by the female (circle) to all of her offspring, including males (squares). Of subsequent offspring, males do not transmit the mutation, but females continue to transmit the mutation to all of their offspring because mitochondria are passed through ova, not sperm. For simplicity, although both parents are shown for the first generation, subsequent generations do not show the genetic partners, who are assumed to lack the mutation. Note: All or only some of the mitochondria may carry the mutation, a variable that affects the clinical expression of the mutation. (See text regarding homoplasmic and heteroplasmic individuals.)
Over 16,000 human genes have been identified or implied through their phenotypes and inheritance patterns in families. This total represents 60–70% of all genes thought to be encoded by the 22 autosomes, two sex chromosomes, and the mitochondrial chromosome. In the 1960s, Victor McKusick and colleagues began an international effort to catalogue human mendelian variation. This persists as Online Mendelian Inheritance in Man (OMIM).
Online Mendelian Inheritance in Man, OMIM®
. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD). http://omim.org
et al. Mitochondrial genes in degenerative diseases, cancer and aging. In: Emery and Rimoin's Principles and Practice of Medical Genetics, 6th ed. Rimoin
et al (editors). Churchill Livingstone, 2014.