• An autosomal recessive phenotype, if not isolated, is typically seen only in the sibship of the proband, not in parents, offspring, or other relatives.
• For most autosomal recessive traits, males and females are equally likely to be affected.
• Parents of an affected child are asymptomatic carriers of pathogenic alleles (obligate carriers).
• The parents of the affected person may in some cases be consanguineous. This is especially likely if the gene responsible for the condition is rare in the population.
• The recurrence risk for each sib of the proband is 1 in 4 (25%).
• Unaffected sibs of proband have a ⅔ chance of being carriers.
Autosomal Dominant Inheritance
More than half of all known mendelian disorders are inherited as autosomal dominant traits. The incidence of some autosomal dominant disorders can be high. For example, adult polycystic kidney disease occurs in 1 in 1000 individuals in the United States. Other autosomal dominant disorders show a high frequency only in certain populations from specific geographic areas (e.g., the frequency of familial hypercholesterolemia affects 1 in 100 for Afrikaner populations in South Africa; myotonic dystrophy affects 1 in 550 in the Charlevoix and Saguenay–Lac Saint Jean regions of northeastern Quebec). The burden of autosomal dominant disorders is further increased because of their hereditary nature; when they are transmitted through families they raise medical and even social problems, not only for individuals but also for whole kindreds, often through many generations.
The risk and severity of dominantly inherited disease in the offspring depend on whether one or both parents are affected and whether the trait is a pure dominant or is incompletely dominant. There are a number of ways that one pathogenic allele can cause a dominantly inherited trait to occur in a heterozygote despite the presence of a normal allele.
Denoting D as the pathogenic variant and d as the wild-type allele, the parents of children with an autosomal dominant disease can be two heterozygotes (D/d) or, more frequently, a heterozygote (D/d) and a homozygote for a normal allele (d/d).
As seen in Table 1, each child born to a couple where one parent has the D/d genotype and the other the d/d genotype has a 50% chance of receiving the affected parent’s allele D and a 50% chance of receiving the normal allele d. In the population as a whole, then, the offspring of D/d by d/d parents are ~50% D/d and 50% d/d. Of course, each pregnancy is an independent event, not governed by the outcome of previous pregnancies. Thus, within a family, the distribution of affected and unaffected children may be quite different from the theoretic expected ratio of 1:1, especially if the sibship is small. Typical autosomal dominant inheritance can be seen in the pedigree of a family with a dominantly inherited form of hereditary deafness (Fig. 1A). In practice, homozygotes for dominant phenotypes are not often seen, but the offspring of two affected individuals with the genotype D/d could have a D/D genotype 25% of the time. The potential to observe individuals with the D/D genotype may also be limited if the phenotype causes early lethality (see the description of incompletely dominant inheritance later).
Table1. Autosomal Dominant Inheritance
Fig1. (A) Pedigree showing typical inheritance of a form of adult-onset progressive sensorineural hearing loss (DFNA1) inherited as an autosomal dominant trait. (B) Pedigree showing inheritance of achondroplasia, an incompletely dominant (or semidominant) trait. (C) Pedigree showing a sporadic case of thanatophoric dwarfism, a genetic lethal, in the proband (arrow).
Pure Dominant Inheritance
As mentioned earlier, very few human disorders demonstrate a purely dominant pattern of inheritance. Even Huntington disease, which is frequently considered to be a pure dominant because the nature and severity of symptoms in heterozygotes and homozygotes is similar, appears to have a somewhat accelerated time course from onset to death in homozygous individuals, compared with that of heterozygotes.
Incompletely Dominant Inheritance
As introduced in Chapter 4, achondroplasia is an incompletely dominant skeletal disorder (short limbed dwarfism and large head) caused by certain variants in the fibroblast growth factor receptor 3 gene (FGFR3). Most individuals with achondroplasia have normal intelligence and lead normal lives within their physical capabilities. A pedigree with two parents heterozygous for the most common pathogenic variant that causes achondroplasia is shown in Fig. 2B. The deceased child, individual III-3, was a homozygote for the condition and had a disorder far more severe than in either parent, resulting in death soon after birth.
Sex-Limited Phenotype in Autosomal Dominant Disease
As discussed earlier for the autosomal recessive condition, hemochromatosis, autosomal dominant phenotypes may also demonstrate a sex ratio that differs significantly from 1:1. Extreme divergence of the sex ratio is seen in sex-limited phenotypes, in which the defect is transmitted as an autosomal trait but expressed in only one sex. An example is male-limited precocious puberty, an autosomal dominant disorder in which affected boys develop secondary sexual characteristics and undergo an adolescent growth spurt at ~4 years of age. In some families, the cause has been traced to variants in the LCGR gene, which encodes the receptor for luteinizing hormone; these pathogenic variants constitutively activate the receptor’s signaling action, even in the absence of its hormone. The defect shows no effect in heterozygous females. The pedigree in Fig. 2 shows that, although the disease can be transmit ted by unaffected (nonpenetrant carrier) females, it can also be transmitted directly from father to son, showing that it is autosomal, not X linked.
Fig2. Part of a large pedigree of male-limited precocious puberty. This autosomal dominant disorder can be transmitted by affected males or by unaffected carrier females. Male-to-male transmission shows that inheritance is autosomal, not X linked. Transmission of the trait through carrier females shows that inheritance cannot be Y linked. Arrow indicates proband.
For disorders in which affected males do not repro duce, however, it is not always easy to distinguish sex limited autosomal inheritance from X-linked inheritance, because the critical evidence—absence of male-to-male transmission, cannot be provided. In that case, other lines of evidence, particularly gene mapping to learn whether the responsible gene maps to the X chromosome or to an autosome, can determine the pattern of inheritance and the consequent recurrence risk (Box 1).
Box1. CHARACTERISTICS OF AUTOSOMAL DOMINANT INHERITANCE
Effect of Incomplete Penetrance, Variable Expressivity, and New Mutations on Autosomal Dominant Inheritance Patterns
Some of the difficulties raised by incomplete penetrance in fully understanding the inheritance of a disease phenotype are demonstrated by the split-hand/foot mal formation, a type of ectrodactyly that can be caused by pathogenic variants in the DLX5 gene (Fig. 3). The split-hand malformation originates in the sixth or seventh week of development, when the hands and feet are forming. Lack of penetrance in pedigrees of split-hand malformation can lead to apparent skipping of generations. This complicates genetic counseling because an at risk person with normal hands may, nevertheless, carry a pathogenic variant associated with the condition and, thus, be capable of having children who are affected.
Fig3. Split-hand deformity, an autosomal dominant trait involving the hands and feet, in a 3-month-old boy. (A) Upper part of body. (B) Lower part of body. (From Kelikian H: Congenital deformities of the hand and forearm, Philadelphia, 1974, WB Saunders.)
Fig. 4 is a pedigree of split-hand deformity in which the unaffected sister of an affected man sought genetic counseling. Her mother is a nonpenetrant carrier of the split-hand variant. The literature on split-hand deformity suggests that there is reduced penetrance of ~80% (i.e., only 80% of the people who have the variant exhibit the clinical defect). Using this pedigree information to calculate conditional prob abilities, one can calculate that the risk that the consultant might herself be a nonpenetrant carrier is 17% and her chance of having a child with the abnormality is therefore ~7% (carrier risk × the risk for transmission × penetrance, or 17% × 50% × 80%).
Fig4. Pedigree of split-hand deformity demonstrating of non-penetrance in the mother of the proband (arrow) and his sister, the consultand. Reduced penetrance must be taken into account in genetic counseling.
An autosomal dominant inheritance pattern may also be obscured by variable expressivity. Neurofibromatosis 1 (NF1), a common disorder of the nervous system, demonstrates both age-dependent penetrance and variable expressivity in a single family. Some adults may have only multiple flat, irregular pigmented skin lesions, known as café au lait spots, and small benign tumors (hamartomas) called Lisch nodules on the iris of the eye. Other family members can have these signs as well as multiple benign fleshy tumors (neurofibromas) in the skin. Still others may have a much more severe phenotype, with intellectual disability, diffuse plexiform neurofibromas, or malignant tumors of nervous system or muscle in addition to the café au lait spots, Lisch nod ules, and neurofibromas. Unless one looks specifically for mild manifestations of the disease in the relatives of the proband, heterozygous carriers may be incorrectly classified as unaffected, noncarriers.
Furthermore, the signs of NF1 may require many years to develop. For example, in the newborn period, less than half of all affected newborns show even the most subtle sign of the disease: an increased incidence of café au lait spots. Eventually, however, multiple café au lait spots and Lisch nodules do appear, so that by adulthood, heterozygotes always demonstrate some sign of the disease. The challenges for diagnosis and genetic counseling in NF1 are presented in.
Finally, in classic autosomal dominant inheritance, every affected person in a pedigree has an affected parent, who also has an affected parent, and so on, as far back as the disorder can be traced (see Fig. 1A). In fact, however, many dominant conditions of medical importance occur because of a spontaneous, de novo mutation in a gamete inherited from a noncarrier parent (see Fig. 1C). An individual with an autosomal dominant disorder caused by a new mutation will look like an isolated case, and his or her parents, aunts and uncles, and cousins will all be unaffected noncarriers. This person will still be at risk for passing the altered allele down to his or her own children, however. Once a new mutation has arisen, the variant allele will be transmitted to future generations following standard principles of inheritance; as we discuss in the next section, its survival in the population depends on the fitness of persons carrying it.
Relationship Between New Mutation and Fitness in Autosomal Dominant Disorders
In many disorders, whether a condition demonstrates an obvious pattern of transmission in families depends on whether individuals affected by the disorder can repro duce. Geneticists coined the term fitness as a measure of the impact of a condition on reproduction. Fitness is defined as the ratio of the number of offspring of individuals affected with the condition who survive to reproductive age, compared to the number of offspring of individuals who do not carry the pathogenic allele. Fitness ranges from 0 (affected individuals never have children who survive to reproductive age) to 1 (affected individuals have the same number of offspring as unaffected controls). Although we will explore the impact of mutation, selection, and fitness on allele frequencies in greater detail in Chapter 10, here we discuss examples that illustrate the major concepts and range of impact of fitness on autosomal dominant conditions.
At one extreme are disorders that have a fitness of 0; patients with such disorders never reproduce, and the disorder is referred to as genetic lethal. One example is the severe short-limb dwarfism syndrome known as thanatophoric dysplasia that occurs in heterozygotes for certain pathogenic alterations in the FGFR3 gene (see Fig. 1C). Thanatophoric dysplasia is lethal in the neonatal period, and therefore all probands with the disorder must be due to new mutations because these variants cannot be transmitted to the next generation.
At the other extreme are disorders that have virtually normal reproductive fitness because of a late age of onset or a mild phenotype that does not interfere with repro duction. If the fitness is normal, the disorder will only rarely be the result of new mutation; a patient is much more likely to have inherited the pathogenic variant, and the pedigree is likely to show multiple affected individuals with clear-cut autosomal dominant inheritance. Late onset progressive hearing loss is a good example of such an autosomal dominant condition, with a fitness of ~1 (see Fig. 1A). Thus, there is an inverse relation between the fitness of a given autosomal dominant disorder and the proportion of individuals with the disorder who inherited the defective gene, versus those who received it due to a new mutation. The measurement of mutation frequency and the relation of mutation frequency to fit ness will be discussed further in Chapter 10.
It is important to note that fitness is not simply a measure of physical or intellectual disability. Some individuals with an autosomal dominant disorder may appear phenotypically normal but have a fitness of 0; at the other extreme, individuals may have normal or near normal fitness, despite being affected by an autosomal dominant condition with an obvious and severe phenotype, such as familial Alzheimer disease.
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