Thompson & Thompson Genetics in Medicine, 8th Edition

CHAPTER 7. Patterns of Single-Gene Inheritance

In Chapter 1, we introduced and briefly characterized the three main categories of genetic disorders—single-gene, chromosomal, and complex. In this chapter, the typical patterns of transmission of single-gene disorders are discussed in detail, building on the mechanisms of gene and genome transmission presented generally in Chapters 2 and 3; the emphasis here is on the various inheritance patterns of genetic disease in families. Later, in Chapter 8, we will examine more complex patterns of inheritance, including multifactorial disorders that result from the interaction between variants at one or more genes, as well as environmental factors.

Overview and Concepts

Genotype and Phenotype

For autosomal loci (and X-linked loci in females), the genotype of a person at a locus consists of both of the alleles occupying that locus on the two homologous chromosomes (Fig. 7-1). Genotype should not be confused with haplotype, which refers to the set of alleles at two or more neighboring loci on one of the two homologous chromosomes. More broadly, the term genotype can refer to all of the allele pairs that collectively make up an individual's genetic constitution across the entire genome. Phenotype, as described initially in Chapter 3, is the expression of genotype as a morphological, clinical, cellular, or biochemical trait, which may be clinically observable or may only be detected by blood or tissue testing. The phenotype can be discrete—such as the presence or absence of a disease—or can be a measured quantity, such as body mass index or blood glucose levels. A phenotype may, of course, be either normal or abnormal in a given individual, but in this book, which emphasizes disorders of medical significance, the focus is on disease phenotypes—that is, genetic disorders.


FIGURE 7-1 The concepts of genotype and phenotype. (Left) The genotype refers to information encoded in the genome. Diagram of one pair of homologous chromosomes and two loci on that chromosome, Locus 1 and Locus 2, in an individual who is heterozygous at both loci. He has alleles A and aat locus 1 and alleles B and b at locus 2. The locus 1 genotype is Aa, while the locus 2 genotype is Bb. The two haplotypes on these homologous chromosomes are A-B and a-b(Right) The phenotype is the physical, clinical, cellular, or biochemical manifestation of the genotype, as illustrated here by morphometric aspects of an individual’s face.

When a person has a pair of identical alleles at a locus encoded in nuclear DNA, he or she is said to be homozygous, or a homozygote; when the alleles are different and one of the alleles is the wild-type allele, he or she is heterozygous, or a heterozygote. The term compound heterozygote is used to describe a genotype in which two different mutant alleles of a gene are present, rather than one wild-type and one mutant allele. These terms (homozygousheterozygous, and compound heterozygous) can be applied either to a person or to a genotype. In the special case in which a male has an abnormal allele for a gene located on the X chromosome and there is no other copy of the gene, he is neither homozygous nor heterozygous but is referred to as hemizygous. Mitochondrial DNA is still another special case. In contrast to the two copies of each gene per diploid cell, mitochondrial DNA molecules, and the genes encoded by the mitochondrial genome, are present in tens to thousands of copies per cell (see Chapter 2). For this reason, the terms homozygous, heterozygous, and hemizygous are not used to describe genotypes at mitochondrial loci.

single-gene disorder is one that is determined primarily by the alleles at a single locus. The known single-gene diseases are listed in the late Victor A. McKusick's classic reference, Mendelian Inheritance in Man, which has been indispensable to medical geneticists for decades. These diseases follow one of the classic inheritance patterns in families (autosomal recessive, autosomal dominant, X-linked) and are therefore referred to as mendelian because, like the characteristics of the garden peas Gregor Mendel studied, they occur on average in fixed and predictable proportions among the offspring of specific types of matings.

A single abnormal gene or gene pair often produces multiple diverse phenotypic effects in multiple organ systems, with a variety of signs and symptoms occurring at different points during the life span. To cite just one example, individuals with a mutation in the VHL gene can have hemangioblastomas of the brain, spinal cord, and retina; renal cysts; pancreatic cysts; renal cell carcinoma; pheochromocytoma; and endolymphatic tumors of the inner ear; as well as tumors of the epididymis in males or of the broad ligament of the uterus in females—even though all of these disease manifestations stem from the same single mutation. Under these circumstances, the disorder is said to exhibit pleiotropy (from Greek pleion and tropos, more turns), and the expression of the gene defect is said to be pleiotropic. At present, for many pleiotropic disorders, the connection between the gene defect and the various manifestations is neither obvious nor well understood.

Single-gene disorders affect children disproportionately, but not exclusively. Serious single-gene disorders affect 1 in 300 neonates and are responsible for an estimated 7% of pediatric hospitalizations. Although less than 10% of single-gene disorders manifest after puberty, and only 1% occur after the end of the reproductive period, mendelian disorders are nonetheless important to consider in adult medicine. There are nearly 200 mendelian disorders whose phenotypes include common adult illnesses such as heart disease, stroke, cancer, and diabetes. Although mendelian disorders are by no means the major contributory factor in causing these common diseases in the population at large, they are important in individual patients because of their significance for the health of other family members and because of the availability of genetic testing and detailed management options for many of them.

Penetrance and Expressivity

For some genetic conditions, a disease-causing genotype is always fully expressed at birth as an abnormal phenotype. Clinical experience, however, teaches that other disorders are not expressed at all or may vary substantially in their signs and symptoms, clinical severity, or age of onset, even among members of a family who all share the same disease-causing genotype. Geneticists use distinct terms to describe such differences in clinical expression.

Penetrance is the probability that a mutant allele or alleles will have any phenotypic expression at all. When the frequency of expression of a phenotype is less than 100%—that is, when some of those who have the relevant genotype completely fail to express it—the disorder is said to show reduced or incomplete penetrance. Penetrance is all or nothing. It is the percentage of people at any given age with a predisposing genotype who are affected, regardless of the severity.

Penetrance of some disorders is age dependent; that is, it may occur any time, from early in intrauterine development all the way to the postreproductive years. Some disorders are lethal prenatally, whereas others can be recognized prenatally (e.g., by ultrasonography; see Chapter 17) but are consistent with a liveborn infant; still others may be recognized only at birth (congenital).* Other disorders have their onset typically or exclusively in childhood or in adulthood. Even in these, however, and sometimes even in the same family, two individuals carrying the same disease-causing genotype may develop the disease at very different ages.

In contrast to penetrance, expressivity refers not to the presence or absence of a phenotype, but to the severity of expression of that phenotype among individuals with the same disease-causing genotype. When the severity of disease differs in people who have the same genotype, the phenotype is said to show variable expressivity. Even in the same family, two individuals carrying the same mutant genes may have some signs and symptoms in common, whereas their other disease manifestations may be quite different, depending on which tissues or organs happen to be affected. The challenge to the clinician caring for these families is to not miss very subtle signs of a disorder in a family member and, as a result, either mistake mild expressivity for lack of penetrance or infer that the individual does not have the disease-causing genotype.


Single-gene disorders are characterized by their patterns of transmission in families. To establish the pattern of transmission, a usual first step is to obtain information about the family history of the patient and to summarize the details in the form of a pedigree, a graphical representation of the family tree, with use of standard symbols (Fig. 7-2). The extended family depicted in such pedigrees is a kindred (Fig. 7-3). An affected individual through whom a family with a genetic disorder is first brought to the attention of the geneticist (i.e., is ascertained) is the probandpropositus, or index case. The person who brings the family to attention by consulting a geneticist is referred to as the consultand; the consultand may be an affected individual or an unaffected relative of a proband. A family may have more than one proband, if they are ascertained through more than one source. Brothers and sisters are called sibs or siblings, and a family of sibs forms a sibship. Relatives are classified as first degree (parents, sibs, and offspring of the proband), second degree (grandparents and grandchildren, uncles and aunts, nephews and nieces, and half-sibs), or third degree (e.g., first cousins), and so forth, depending on the number of steps in the pedigree between the two relatives. The offspring of first cousins are second cousins, and a child of a first cousin is a “first cousin once removed” of his or her parents' first cousins. Couples who have one or more ancestors in common are consanguineous. If the proband is the only affected member in a family, he or she is an isolated case (see Fig. 7-3). If an isolated case is proven to be due to new mutation in the proband, it is referred to as a sporadic case. When there is a definitive diagnosis based on comparisons to other patients, well-established patterns of inheritance in other families with the same disorder can often be used as a basis for counseling, even if the patient is an isolated case in the family. Thus, even when a patient has no similarly affected relatives, it may still be possible to recognize that the disorder is genetic and determine the risk to other family members.


FIGURE 7-2 Symbols commonly used in pedigree charts. Although there is no uniform system of pedigree notation, the symbols used here are according to recent recommendations made by professionals in the field of genetic counseling.


FIGURE 7-3 Relationships within a kindred. The proband, III-5 (arrow), represents an isolated case of a genetic disorder. She has four siblings, III-3, III-4, III-7, and III-8. Her partner/spouse is III-6, and they have three children (their F1 progeny). The proband has nine first-degree relatives (her parents, siblings, and offspring), nine second-degree relatives (grandparents, uncles and aunts, nieces and nephews, and grandchildren), two third-degree relatives (first cousins), and four fourth-degree relatives (first cousins once removed). IV-3, IV-5, and IV-6 are second cousins of IV-1 and IV-2. IV-7 and IV-8, whose parents are consanguineous, are doubly related to the proband: second-degree relatives through their father and fourth-degree relatives through their mother.

Examining a pedigree is an essential first step in determining the inheritance pattern of a genetic disorder in a family. There are, however, a number of situations that may make the inheritance pattern of an individual pedigree difficult to discern. The inheritance pattern in a family with a lethal disorder affecting a fetus early in pregnancy may be obscure because all that one observes are multiple miscarriages or reduced fertility. Conversely, for phenotypes with variable age of onset, an affected individual may have unaffected family members who have not yet reached the age at which the mutant gene reveals itself. In addition to reduced penetrance or variable expressivity that may mask the existence of relatives carrying the mutant genotype, the geneticist may lack accurate information about the presence of the disorder in relatives or about family relationships. Finally, with the small family size typical of most developed countries today, the patient may by chance alone be the only affected family member, making determination of any inheritance pattern very difficult.

Mendelian Inheritance

The patterns of inheritance shown by single-gene disorders in families depend chiefly on two factors:

• Whether the chromosomal location of the gene locus is on an autosome (chromosomes 1 to 22), on a sex chromosome (X and Y chromosomes), or in the mitochondrial genome

• Whether the phenotype is dominant (expressed when only one chromosome carries the mutant allele) or recessive (expressed only when both chromosomes of a pair carry mutant alleles at a locus)

Autosomal, X-Linked, and Mitochondrial Inheritance

The different patterns of transmission of the autosomes, sex chromosomes, and mitochondria during meiosis result in distinctive inheritance patterns of mutant alleles on these different types of chromosome (see Chapter 2). Because only one of the two copies of each autosome passes into a single gamete during meiosis, males and females heterozygous for a mutant allele on an autosome have a 50% chance of passing that allele on to any offspring, regardless of the child's sex. Mutant alleles on an X chromosome, however, are not distributed equally to sons and daughters. Males pass their Y chromosome to their sons and their X to their daughters; they therefore cannot pass an allele on the X chromosome to their sons and always pass the allele to their daughters (unless it is at one of the pseudoautosomal loci; see Chapter 6). Because mitochondria are inherited from the mother only, regardless of the sex of the offspring, mutations in the mitochondrial genome are not inherited according to a mendelian pattern. Autosomal, X-linked, and mitochondrial inheritance will be discussed in the rest of the chapter that follows.

Dominant and Recessive Traits

Autosomal Loci

As classically defined, a phenotype is recessive if it is expressed only in homozygotes, hemizygotes, or compound heterozygotes, all of whom lack a wild-type allele, and never in heterozygotes, who do have a wild-type allele. In contrast, a dominant inheritance pattern occurs when a phenotype is expressed in heterozygotes as well as in homozygotes (or compound heterozygotes). For the vast majority of inherited dominant diseases, homozygotes or compound heterozygotes for mutant alleles at autosomal loci are more severely affected than are heterozygotes, an inheritance pattern known as incompletely dominant (or semidominant). Very few diseases are known in which homozygotes (or compound heterozygotes) show the same phenotype as heterozygotes; in such cases, the disorder is referred to as a pure dominantdisease. Finally, if phenotypic expression of both alleles at a locus occurs in a compound heterozygote, inheritance is termed codominant.

ABO Blood Group.

One medically important trait that demonstrates codominant expression is the ABO blood group system important in blood transfusion and tissue transplantation. The A, B, and O alleles at the ABO locus form a three-allele system in which two alleles (A and B) govern expression of either the A or B carbohydrate antigen on the surface of red cells as a codominant trait; a third allele (O) results in expression of neither the A nor the B antigen and is recessive. The difference between the A and B antigen is which of two different sugar molecules makes up the terminal sugar on a cell surface glycoprotein called H. Whether the A or B form of the glycoprotein is made is specified by an enzyme encoded by the ABO gene that adds one or the other sugar molecule to the H antigen depending on which version of the enzyme is encoded by alleles at the ABO locus. There are therefore four phenotypes possible: O, A, B, and AB (Table 7-1). Type A individuals have antigen A on their red blood cells, type B individuals have antigen B, type AB individuals have both antigens, and type O individuals have neither.


ABO Genotypes and Serum Reactivity


− Represents no reaction; + represents reaction. RBC, red blood cell.

A feature of the ABO groups not shared by other blood group systems is the reciprocal relationship, in an individual, between the antigens present on the red blood cells and the antibodies in the serum (see Table 7-1). When the red blood cells lack antigen A, the serum contains anti-A antibodies; when the cells lack antigen B, the serum contains anti-B. Formation of anti-A and anti-B antibodies in the absence of prior blood transfusion is believed to be a response to the natural occurrence of A-like and B-like antigens in the environment (e.g., in bacteria).

X-Linked Loci

For X-linked disorders, a condition expressed only in hemizygotes and never in heterozygotes has traditionally been referred to as an X-linked recessive, whereas a phenotype that is always expressed in heterozygotes as well as in hemizygotes has been called X-linked dominant. Because of epigenetic regulation of X-linked gene expression in carrier females due to X chromosome inactivation (introduced in Chapters 3 and 6), it can be difficult to determine phenotypically if a disease with an X-linked inheritance pattern is dominant or recessive, and some geneticists have therefore chosen not to use these terms when describing the inheritance of X-linked disease.

Strictly speaking, the terms dominant and recessive refer to the inheritance pattern of a phenotype rather than to the alleles responsible for that phenotype. Similarly, a gene is not dominant or recessive; it is the phenotype produced by a particular mutant allele in that gene that shows dominant or recessive inheritance.

Autosomal Patterns of Mendelian Inheritance

Autosomal Recessive Inheritance

Autosomal recessive disease occurs only in individuals with two mutant alleles and no wild-type allele. Such homozygotes must have inherited a mutant allele from each parent, each of whom is (barring rare exceptions that we will consider later) a heterozygote for that allele.

When a disorder shows recessive inheritance, the mutant allele responsible generally reduces or eliminates the function of the gene product, a so-called loss-of-function mutation. For example, many recessive diseases are caused by mutations that impair or eliminate the function of an enzyme. The remaining normal gene copy in a heterozygote is able to compensate for the mutant allele and prevent the disease from occurring. However, when no normal allele is present, as in homozygotes or compound heterozygotes, disease occurs. Disease mechanisms and examples of recessive conditions are discussed in detail in Chapters 11 and 12.

Three types of matings can lead to homozygous offspring affected with an autosomal recessive disease. The most common mating by far is between two unaffected heterozygotes, who are often referred to as carriers. However, any mating in which each parent has at least one recessive allele can produce homozygous affected offspring. The transmission of a recessive condition can be followed if we symbolize the mutant recessive allele as r and its normal dominant allele as R.

Autosomal Recessive Inheritance


The wild-type allele is denoted by uppercase R, a mutant allele by lowercase r.

As seen in the table, when both parents of an affected person are carriers, their children's risk for receiving a recessive allele is 50% from each parent. The chance of inheriting two recessive alleles and therefore being affected is thus image × image or 1 in 4 with each pregnancy. The 25% chance for two heterozygotes to have a child with an autosomal recessive disorder is independent of how many previous children there are who are either affected or unaffected. The proband may be the only affected family member, but if any others are affected, they are usually in the same sibship and not elsewhere in the kindred (Fig. 7-4).


FIGURE 7-4 Typical pedigree showing autosomal recessive inheritance.

Sex-Influenced Autosomal Recessive Disorders

Because males and females both have the same complement of autosomes, autosomal recessive disorders generally show the same frequency and severity in males and females. There are, however, exceptions. Some autosomal recessive diseases demonstrate a sex-influenced phenotype, that is, the disorder is expressed in both sexes but with different frequencies or severity. For example, hereditary hemochromatosisis an autosomal recessive phenotype that is 5 to 10 times more common in males than in females (Case 20). Affected individuals have enhanced absorption of dietary iron that can lead to iron overload and serious damage to the heart, liver, and pancreas. The lower incidence of the clinical disorder in homozygous females is believed to be due to their lower dietary iron intake, lower alcohol usage, and increased iron loss through menstruation.

Gene Frequency and Carrier Frequency

Mutant alleles responsible for a recessive disorder are generally rare, and so most people will not have even one copy of the mutant allele. Because an autosomal recessive disorder must be inherited from bothparents, the risk that any carrier will have an affected child depends partly on the chance that his or her mate is also a carrier of a mutant allele for the condition. Thus knowledge of the carrier frequency of a disease is clinically important for genetic counseling.

The most common autosomal recessive disorder in white children is cystic fibrosis (CF) (Case 12), caused by mutations in the CFTR gene (see Chapter 12). Among white populations, approximately 1 child in 2000 has two mutant CFTR alleles and has the disease, from which we can infer that 1 in 23 individuals is a silent carrier who has no disease. (How one calculates heterozygote frequencies in autosomal recessive conditions will be addressed in Chapter 9.) Mutant alleles may be handed down from carrier to carrier for numerous generations without ever appearing in the homozygous state and causing overt disease. The presence of such hidden recessive genes is not revealed unless the carrier happens to mate with someone who also carries a mutant allele at the same locus and the two deleterious alleles are both inherited by a child.

Estimates of the number of deleterious alleles in each of our genomes range from 50 to 200 based on examining an individual's complete exome or genome sequence for clearly deleterious mutations in the coding regions of the genome (see Chapter 4). This estimate is imprecise, however. It may be an underestimate, because it does not include mutant alleles whose deleterious effect is not obvious from a simple examination of the DNA sequence. It may also, however, be an overestimate, because it includes mutations in many genes that are not known to cause disease.


Because most mutant alleles are generally uncommon in the population, people with rare autosomal recessive disorders are typically compound heterozygotes rather than true homozygotes. One well-recognized exception to this rule occurs when an affected individual inherits the exact same mutant allele from both parents because the parents are consanguineous (i.e., they are related and carry the identical mutant allele inherited from a common ancestor). Finding consanguinity in the parents of a patient with a genetic disorder is strong evidence (although not proof) for the autosomal recessive inheritance of that condition. For example, the disorder in the pedigree in Figure 7-5 is likely to be an autosomal recessive trait, even though other information in the pedigree may seem insufficient to establish this inheritance pattern.


FIGURE 7-5 Pedigree in which parental consanguinity suggests autosomal recessive inheritance. Arrow indicates the proband.

Consanguinity is more frequently found in the background of patients with very rare conditions than in those with more common recessive conditions. This is because it is less likely that two individuals mating at random in the population will both be carriers of a very rare disorder by chance alone than it is that they would both be carriers because they inherited the same mutant allele from a single common ancestor. For example, in xeroderma pigmentosum (Case 48), a very rare autosomal recessive condition of DNA repair (see Chapter 15), more than 20% of cases occur among the offspring of marriages between first cousins. In contrast, in more common recessive conditions, most cases of the disorder result from matings between unrelated persons, each of whom happens by chance to be a carrier. Thus most affected persons with a relatively common disorder, such as CF, are not the result of consanguinity, because the mutant allele is so common in the general population. How consanguinity is measured for different matings is described in Chapter 9.

The genetic risk to the offspring of marriages between related people is not as great as is sometimes imagined. For marriages between first cousins, the absolute risks of abnormal offspring, including not only known autosomal recessive diseases but also stillbirth, neonatal death, and congenital malformation, is 3% to 5%, approximately double the overall background risk of 2% to 3% for offspring born to any unrelated couple (see Chapter 16). Consanguinity at the level of third cousins or more remote relationships is not considered to be genetically significant, and the increased risk for abnormal offspring is negligible in such cases.

The incidence of first-cousin marriage is low (≈1 to 10 per 1000 marriages) in many populations in Western societies today. However, it remains relatively common in some ethnic groups, for example, in families from rural areas of the Indian subcontinent, in other parts of Asia, and in the Middle East, where between 20% and 60% of all marriages are between cousins.

Characteristics of Autosomal Recessive Inheritance

• An autosomal recessive phenotype, if not isolated, is typically seen only in the sibship of the proband, and not in parents, offspring, or other relatives.

• For most autosomal recessive diseases, males and females are equally likely to be affected.

• Parents of an affected child are asymptomatic carriers of mutant alleles.

• 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%).

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 (Case 37) occurs in 1 in 1000 individuals in the United States. Other autosomal dominant disorders show a high frequency only in certain populations from specific geographical areas: for example, the frequency of familial hypercholesterolemia (Case 16is 1 in 100 for Afrikaner populations in South Africa and of myotonic dystrophy is 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 different ways that one mutant allele can cause a dominantly inherited trait to occur in a heterozygote despite the presence of a normal allele. Disease mechanisms in various dominant conditions are discussed in Chapter 12.

Denoting D as the mutant allele and d as the wild-type allele, matings that produce children with an autosomal dominant disease can be between two heterozygotes (D/d) for the mutation or, more frequently, between a heterozygote for the mutation (D/d) and a homozygote for a normal allele (d/d).

Autosomal Dominant Inheritance


The mutant allele causing dominantly inherited disease is denoted by uppercase D; the normal or wild-type allele is denoted by lowercase d.

As seen in the table, each child of a D/d by d/d mating has a 50% chance of receiving the affected parent's abnormal 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 approximately 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 theoretical 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. 7-6A).


FIGURE 7-6 A, Pedigree showing typical inheritance of a form of adult-onset progressive sensorineural deafness (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).

In medical practice, homozygotes for dominant phenotypes are not often seen because matings that could produce homozygous offspring are rare. Again denoting the abnormal allele as D and the wild-type allele as d, the matings that can produce a D/D homozygote might theoretically be D/d by D/d, D/D by D/d, or D/D by D/D. In the case of two heterozygotes mating, three fourths of the offspring of a D/d by D/dmating will be affected to some extent and one fourth unaffected.

Pure Dominant Inheritance

As mentioned earlier, very few human disorders demonstrate a purely dominant pattern of inheritance. Even Huntington disease (Case 24), which is frequently considered to be a pure dominant because the disease is generally similar in the nature and severity of symptoms in heterozygotes and homozygotes, appears to have a somewhat accelerated time course from the onset of disease to death in homozygous individuals compared with heterozygotes.

Incompletely Dominant Inheritance

As introduced in Chapter 4achondroplasia (Case 2) is an incompletely dominant skeletal disorder of short-limbed dwarfism and large head caused by certain mutations in the fibroblast growth factor receptor 3 gene (FGFR3). Most achondroplasia patients have normal intelligence and lead normal lives within their physical capabilities. Marriages between two patients with achondroplasia are not uncommon. A pedigree of a mating between two individuals heterozygous for the most common mutation that causes achondroplasia is shown in Figure 7-6B. 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 autosomally transmitted 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 approximately 4 years of age (Fig. 7-7). In some families, the defect has been traced to mutations in the LCGRgene, which encodes the receptor for luteinizing hormone; these mutations 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 Figure 7-8 shows that, although the disease can be transmitted by unaffected (nonpenetrant carrier) females, it can also be transmitted directly from father to son, showing that it is autosomal, not X-linked.


FIGURE 7-7 Male-limited precocious puberty, a sex-limited autosomal dominant disorder expressed exclusively in males. This child, at 4.75 years, is 120 cm in height (above the 97th percentile for his age). Note the muscle bulk and precocious development of the external genitalia. Epiphyseal fusion occurs at an early age, and affected persons are relatively short as adults.


FIGURE 7-8 Part of a large pedigree of male-limited precocious puberty in the family of the child shown in Figure 7-7. 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 reproduce, 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 (see Chapter 10), can determine the pattern of inheritance and the consequent recurrence risk (see Box).

Characteristics of Autosomal Dominant Inheritance

• The phenotype usually appears in every generation, each affected person having an affected parent. Exceptions or apparent exceptions to this rule in clinical genetics are (1) cases originating from fresh mutations in a gamete of a phenotypically normal parent and (2) cases in which the disorder is not expressed (nonpenetrant) or is expressed only subtly in a person who has inherited the responsible mutant allele.

• Any child of an affected parent has a 50% risk for inheriting the trait. This is true for most families, in which the other parent is phenotypically normal. Because statistically each family member is the result of an “independent event,” wide deviation from the expected 1 : 1 ratio may occur by chance in a single family.

• Phenotypically normal family members do not transmit the phenotype to their children. Failure of penetrance or subtle expression of a condition may lead to apparent exceptions to this rule.

• Males and females are equally likely to transmit the phenotype, to children of either sex. In particular, male-to-male transmission can occur, and males can have unaffected daughters.

• A significant proportion of isolated cases are sporadic cases due to new mutation. The less the fitness, the greater is the proportion of cases due to new mutation.

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 malformation, a type of ectrodactyly (Fig. 7-9). The split-hand malformation originates in the sixth or seventh week of development, when the hands and feet are forming. Failure of penetrance in pedigrees of split-hand malformation can lead to apparent skipping of generations, and this complicates genetic counseling because an at-risk person with normal hands may nevertheless carry the mutation for the condition and thus be capable of having children who are affected.


FIGURE 7-9 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. SeeSources & Acknowledgments.

Figure 7-10 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 mutation. The literature on split-hand deformity suggests that there is reduced penetrance of approximately 70% (i.e., only 70% of the people who have the mutation exhibit the clinical defect). Using this pedigree information to calculate conditional probabilities (as discussed further in Chapter 16), one can calculate that the risk that the consultand might herself be a nonpenetrant carrier is 23% and her chance of having a child with the abnormality is therefore approximately 8% (carrier risk × the risk for transmission × penetrance, or 23% × 50% × 70%).


FIGURE 7-10 Pedigree of split-hand deformity demonstrating failure of 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. And, 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 nodules, 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 (Case 34).

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. 7-6A). 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. 7-6C). An individual with an autosomal dominant disorder caused by new mutation will look like an isolated case, and his or her parents, aunts and uncles, and cousins will all be unaffected noncarriers. He or she will still be at risk for passing the mutation down to his or her own children, however. Once a new mutation has arisen, it will be transmitted to future generations following standard principles of inheritance, and, 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 or not a condition demonstrates an obvious pattern of transmission in families depends on whether individuals affected by the disorder can reproduce. 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 mutant 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 9, 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 a genetic lethal. One example is the severe short-limb dwarfism syndrome known as thanatophoric dwarfism that occurs in heterozygotes for mutations in the FGFR3 gene (see Fig. 7-6C). Thanatophoric dwarfism is lethal in the neonatal period, and therefore all probands with the disorder must be due to new mutations because these mutations 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 reproduction. If the fitness is normal, the disorder will only rarely be the result of fresh mutation; a patient is much more likely to have inherited the disorder than to have a new mutant gene, 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 approximately 1 (see Fig. 7-6A). Thus there is an inverse relation between the fitness of a given autosomal dominant disorder and the proportion of all patients with the disorder who inherited the defective gene versus those who received it as a new mutation. The measurement of mutation frequency and the relation of mutation frequency to fitness will be discussed further in Chapter 9.

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; and 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 (Case 4).

X-Linked Inheritance

In contrast to genes on the autosomes, genes on the X and Y chromosomes are distributed unequally to males and females in families. The patrilineal inheritance of the Y chromosome is straightforward. However, there are very few strictly Y-linked genes, almost all of which are involved in primary sex determination or the development of secondary male characteristics, as discussed in Chapter 6, and they will not be considered here. Approximately 800 protein-coding and 300 noncoding RNA genes have been identified on the X chromosome to date, of which over 300 genes are presently known to be associated with X-linked disease phenotypes. Phenotypes determined by genes on the X have a characteristic sex distribution and a pattern of inheritance that is usually easy to identify and easy to distinguish from the patterns of autosomal inheritance we just explored.

Because males have one X chromosome but females have two, there are only two possible genotypes in males and four in females with respect to mutant alleles at an X-linked locus. A male with a mutant allele at an X-linked locus is hemizygous for that allele, whereas females may be a homozygote for the wild-type allele, a homozygote for a mutant allele, a compound heterozygote for two different mutant alleles, or a heterozygous carrier of a mutant allele. For example, if XH is the wild-type allele for an X-linked disease gene and a mutant allele, Xh, is the disease allele, the genotypes expected in males and females are as follows:

Genotypes and Phenotypes in X-linked Disease





Hemizygous XH



Hemizygous Xh



Homozygous XH/XH



Heterozygous XH/Xh

Carrier (may or may not be affected)


Homozygous (or compound heterozygous) Xh/Xh


X Inactivation, Dosage Compensation, and the Expression of X-Linked Genes

As introduced in Chapters 3 and 6, X inactivation is a normal physiological process in which most of the genes on one of the two X chromosomes in normal females, but not the genes on the single X chromosome in males, are inactivated in somatic cells, thus equalizing the expression of most X-linked genes in the two sexes. The clinical relevance of X inactivation in X-linked diseases is profound. It leads to females having two cell populations, which express alleles of X-linked genes on one or the other of the two X chromosomes (see Fig. 3-13 and further discussion in Chapter 6). These two cell populations are thus genetically identical but functionally distinct, and both cell populations in human females can be readily detected for some disorders. For example, in Duchenne muscular dystrophy (Case 14), female carriers exhibit typical mosaic expression of their dystrophin immunostaining (Fig. 7-11). Depending on the pattern of random X inactivation of the two X chromosomes, two female heterozygotes for an X-linked disease may have very different clinical presentations because they differ in the proportion of cells that have the mutant allele on the active X in a relevant tissue (as seen in manifesting heterozygotes, as described later).


FIGURE 7-11 Immunostaining for dystrophin in muscle specimens. A, A normal female (×480). B, A male with Duchenne muscular dystrophy (DMD) (×480). C, A carrier female (×240). Staining creates the bright signals seen here encircling individual muscle fibers. Muscle from DMD patients lacks dystrophin staining. Muscle from DMD carriers exhibits both positive and negative patches of dystrophin immunostaining, representing fibers with either the normal or mutant allele on the active X. SeeSources & Acknowledgments.

Recessive and Dominant Inheritance of X-Linked Disorders

As mentioned earlier in this chapter, the use of the terms dominant and recessive is somewhat different in X-linked conditions than we just saw for autosomal disorders. So-called X-linked dominant and recessive patterns of inheritance are typically distinguished on the basis of the phenotype in heterozygous females. Some X-linked phenotypes are consistently apparent clinically, at least to some degree, in carriers and are thus referred to as dominant, whereas others typically are not and are considered to be recessive. The difficulty in classifying an X-linked disorder as dominant or recessive arises because females who are heterozygous for the same mutant allele in a family may or may not demonstrate the disease, depending on the pattern of random X inactivation and the proportion of the cells in pertinent tissues that have the mutant allele on the active or inactive X.

Nearly a third of X-linked disorders are penetrant in some but not all female heterozygotes and cannot be classified as either dominant or recessive. Even for disorders that can be so classified, they show incomplete penetrance that varies as a function of X inactivation patterns, not inheritance patterns. Because clinical expression of an X-linked condition does not depend strictly on the particular gene involved or even the particular mutation in the same family, some geneticists have recommended dispensing altogether with the terms recessive and dominant for X-linked disorders. Be that as it may, the terms are widely applied to X-linked disorders, and we will continue to use them, recognizing that they describe extremes of a continuum of penetrance and expressivity in female carriers of X-linked diseases.

X-Linked Recessive Inheritance

The inheritance of X-linked recessive phenotypes follows a well-defined and easily recognized pattern (Fig. 7-12 and Box). An X-linked recessive mutation is expressed phenotypically in all males who receive it, and, consequently, X-linked recessive disorders are generally restricted to males.


FIGURE 7-12 Pedigree pattern demonstrating an X-linked recessive disorder such as hemophilia A, transmitted from an affected male through females to an affected grandson and great-grandson.

Hemophilia A is a classic X-linked recessive disorder in which the blood fails to clot normally because of a deficiency of factor VIII, a protein in the clotting cascade (Case 21). The hereditary nature of hemophilia and even its pattern of transmission have been recognized since ancient times, and the condition became known as the “royal hemophilia” because of its occurrence among descendants of Britain's Queen Victoria, who was a carrier.

As in the earlier discussion, suppose Xh represents the mutant factor VIII allele causing hemophilia A, and XH represents the normal allele. If a male with hemophilia mates with a normal female, all the sons receive their father's Y chromosome and a maternal X and are unaffected, but all the daughters receive the paternal X chromosome with its hemophilia allele and are obligate carriers. If a daughter of the affected male mates with an unaffected male, four genotypes are possible in the progeny, with equal probabilities:

X-Linked Recessive Inheritance


The wild-type allele at the X-linked hemophilia locus is denoted as XH with an uppercase H, and the mutant allele is denoted as Xh with a lowercase h.

The hemophilia of an affected grandfather, which did not appear in any of his own children, has a 50% chance of appearing in each son of his daughters. It will not reappear among the descendants of his sons, however. A daughter of a carrier has a 50% chance of being a carrier herself (see Fig. 7-12). By chance, an X-linked recessive allele may be transmitted undetected through a series of female carriers before it is expressed in a male descendant.

Characteristics of X-Linked Recessive Inheritance

• The incidence of the trait is much higher in males than in females.

• Heterozygous females are usually unaffected, but some may express the condition with variable severity as determined by the pattern of X inactivation.

• The gene responsible for the condition is transmitted from an affected man through all his daughters. Any of his daughters' sons has a 50% chance of inheriting it.

• The mutant allele is never transmitted directly from father to son, but it is transmitted by an affected male to all his daughters.

• The mutant allele may be transmitted through a series of carrier females; if so, the affected males in a kindred are related through females.

• A significant proportion of isolated cases are due to new mutation.

Affected Females in X-linked Recessive Disease

Although X-linked conditions are classically seen only in males, they can be observed in females under two circumstances. In one, such a female can be homozygous for the relevant disease allele, although most X-linked diseases are so rare that this scenario is highly unlikely unless her parents are consanguineous. However, a few X-linked conditions, such as X-linked color blindness, are sufficiently common that such homozygotes are seen in female offspring of an affected father and a carrier mother.

More commonly, an affected female represents a carrier of a recessive X-linked allele who shows phenotypic expression of the disease and is referred to as a manifesting heterozygote. Whether a female carrier will be a manifesting heterozygote depends on a number of features of X inactivation. First, as we saw in Chapter 3, the choice of which X chromosome is to become inactive is a random one, but it occurs when there is a relatively small number of cells in the developing female embryo. By chance alone, therefore, the fraction of cells in various tissues of carrier females in which the normal or mutant allele happens to remain active may deviate substantially from the expected 50%, resulting in unbalanced or “skewed” X inactivation (see Fig. 6-13A). A female carrier may have signs and symptoms of an X-linked disorder if the skewed inactivation is unfavorable (i.e., a large majority of the active X chromosomes in pertinent tissues happen to contain the deleterious allele).

Favorably unbalanced or skewed inactivation, in which the mutant allele is found preferentially on the inactive X in some or all tissues of an unaffected heterozygous female, also occurs. Such skewed inactivation may simply be due to chance alone, as we just saw (albeit in the opposite direction). However, there are certain X-linked conditions in which there is reduced cell survival or a proliferative disadvantage for those cells that originally had the mutant allele on the active X early in development, resulting in a pattern of highly skewed inactivation that favors cells with the normal allele on the active X in relevant tissues. For example, highly skewed X inactivation is the rule in female carriers of certain X-linked immunodeficiencies, in whom only those early progenitor cells that happen to carry the normal allele on their active X chromosome can populate certain lineages in the immune system.

X-Linked Dominant Inheritance

As discussed earlier, an X-linked phenotype can be described as dominant if it is regularly expressed in heterozygotes. X-linked dominant inheritance can readily be distinguished from autosomal dominant inheritance by the lack of male-to-male transmission, which is impossible for X-linked inheritance because males transmit the Y chromosome, not the X, to their sons.

X-Linked Dominant Inheritance


The wild-type allele at the hypophosphatemic rickets locus is denoted as Xd, and the mutant allele is denoted as XD.

Thus the distinguishing feature of a fully penetrant X-linked dominant pedigree (Fig. 7-13) is that all the daughters and none of the sons of affected males are affected; if any daughter is unaffected or any son is affected, the inheritance must be autosomal, not X-linked. The pattern of inheritance through females is no different from the autosomal dominant pattern; because females have a pair of X chromosomes just as they have pairs of autosomes, each child of an affected female has a 50% chance of inheriting the trait, regardless of sex. Across multiple families with an X-linked dominant disease, the expression is usually milder in heterozygous females, because the mutant allele is located on the inactive X chromosome in a proportion of their cells. Thus most X-linked dominant disorders are incompletely dominant, as is the case with most autosomal dominant disorders (see Box).

Characteristics of X-Linked Dominant Inheritance

• Affected males with normal mates have no affected sons and no normal daughters.

• Both male and female offspring of female carriers have a 50% risk for inheriting the phenotype. The pedigree pattern is similar to that seen with autosomal dominant inheritance.

• Affected females are approximately twice as common as affected males, but affected females typically have milder (although variable) expression of the phenotype.

• One example of an X-linked dominant disorder is X-linked hypophosphatemic rickets (also known as vitamin D–resistant rickets), in which the ability of the kidney tubules to reabsorb filtered phosphate is impaired. This disorder fits the criterion of an X-linked dominant disorder in that both sexes are affected, although the serum phosphate level is less depressed and the rickets less severe in heterozygous females than in affected males.


FIGURE 7-13 Pedigree pattern demonstrating X-linked dominant inheritance.

X-Linked Dominant Disorders with Male Lethality

Although most X-linked conditions are typically apparent only in males, a few rare X-linked defects are expressed exclusively or almost exclusively in females. These X-linked dominant conditions are lethal in males before birth (Fig. 7-14). Typical pedigrees of these conditions show transmission by affected females, who produce affected daughters, normal daughters, and normal sons in equal proportions (1 : 1 : 1); affected males are not seen.


FIGURE 7-14 Pedigree pattern demonstrating X-linked dominant inheritance of a disorder that is lethal in males during the prenatal period.

Rett syndrome (Case 40) is a striking disorder that occurs nearly exclusively in females and meets all criteria for being an X-linked dominant disorder that is usually lethal in hemizygous males. The syndrome is characterized by normal prenatal and neonatal growth and development, followed by the rapid onset of neurological symptoms in affected girls. The disease mechanism is thought to reflect abnormalities in the regulation of a set of genes in the developing brain; the cause of male lethality is unknown but presumably reflects a requirement during early development for at least one functional copy of the MECP2 gene on the X chromosome that is mutated in this syndrome.

X-Linked Dominant Disorders with Male Sparing

Other disorders are manifest only in carrier females because hemizygous males are largely spared the consequences of the mutation they carry. One such disorder is female-limited, X-linked epilepsy and cognitive impairment. Affected females are asymptomatic at birth and appear to be developing normally but then develop seizures, generally in the second year of life, after which development begins to regress. Most affected females go on to be developmentally delayed, which can vary from mild to severe. In contrast, male hemizygotes in the same families are completely unaffected (Fig. 7-15). The disorder is due to loss-of-function mutations in the protocadherin gene 19, an X-linked gene that encodes a cell surface molecule expressed on neurons in the central nervous system.


FIGURE 7-15 Pedigree pattern of familial female epilepsy and cognitive impairment, demonstrating its X-linked dominant inheritance with sparing of males hemizygous for a premature termination mutation in the protocadherin 19 gene.

The explanation for this unusual pattern of inheritance is not clear. It is hypothesized that the epilepsy occurs in females because mosaicism for expression of protocadherin 19, resulting from random X inactivation in the brain, disrupts communication between groups of neurons with and without the cell surface protein. Neurons in males uniformly lack the cell surface molecule, but their brains are apparently spared cell-cell miscommunication by a different, compensating protocadherin.

Relationship between New Mutation and Fitness in X-Linked Disorders

Just as with autosomal dominant disorders, new mutations constitute a significant fraction of isolated cases of many X-linked diseases. Males carrying mutations causing X-linked disorders are exposed to selection that is complete for some disorders, partial for others, and absent for still others, depending on the fitness of the genotype. Males carrying mutant alleles for X-linked disorders such as Duchenne muscular dystrophy (Case 14), a disease of muscle that affects young boys, do not reproduce. Fitness of affected males is currently 0, although the situation may change as a result of advances in research aimed at therapy for affected boys (see Chapter 12). In contrast, patients with hemophilia (Case 21also have reduced fitness, but the condition is not a genetic lethal: affected males have on average approximately 70% as many offspring as unaffected males do, and fitness of affected males is therefore approximately 0.70. This fitness may also increase with improvements in the treatment of this disease.

When fitness is reduced, the mutant alleles that these males carry are lost from the population. In contrast to autosomal dominant conditions, however, mutant alleles for X-linked diseases with reduced fitness may be partially or completely protected from selection when present in females. Thus, even in X-linked disorders with a fitness of 0, less than half of new cases will be due to new mutations. The overall incidence of the disease, then, will be determined both by the transmittal of a mutant allele from a carrier mother and by the rate of de novo mutations at the responsible locus. The balance between new mutation and selection will be discussed more fully from the population genetics perspective in Chapter 9.

Pseudoautosomal Inheritance

As we first saw in Chapter 2, meiotic recombination between X-linked loci only occurs between the two homologous X chromosomes and is therefore restricted to females. X-linked loci do not participate in meiotic recombination in males, who have a Y chromosome and only one X chromosome. There are, however, a small number of contiguous loci located at the tips of the p and q arms of the sex chromosomes that are homologous between the X and Y and do recombine between them in male meiosis. As a consequence, during spermatogenesis, a mutant allele at one of these loci on the X chromosome can be transferred onto the Y chromosome and passed on to male offspring, thereby demonstrating the male-to-male transmission characteristic of autosomal inheritance. Because these unusual loci on the X and Y demonstrate autosomal inheritance but are not located on an autosome, they are referred to as pseudoautosomal loci, and the segments of the X and Y chromosomes where they are located are referred to as the pseudoautosomal regions.

One example of a disease caused by a mutation at a pseudoautosomal locus is dyschondrosteosis, a dominantly inherited skeletal dysplasia with disproportionate short stature and deformity of the forearms. Although a greater prevalence of the disease in females as compared with males initially suggested an X-linked dominant disorder, the presence of male-to-male transmission clearly ruled out strict X-linked inheritance (Fig. 7-16). Mutations in the SHOX gene, located in the pseudoautosomal region on Xp and Yp, have been found responsible for this condition.


FIGURE 7-16 Pedigree showing inheritance of dyschondrosteosis due to mutations in SHOX, a pseudoautosomal gene on the X and Y chromosomes. The arrow shows a male who inherited the trait on his Y chromosome from his father. His father, however, inherited the trait on his X chromosome from his mother. SeeSources & Acknowledgments.


Although we are used to thinking of ourselves as being composed of cells that all carry exactly the same complement of genes and chromosomes, this is in reality an oversimplified view. Mosaicism is the presence in an individual or a tissue of at least two cell lineages that differ genetically but are derived from a single zygote. Mutations that occur after conception in a single cell in either prenatal or postnatal life can give rise to clones of cells genetically different from the original zygote because, given the nature of DNA replication, the mutation will persist in all the clonal descendants of that cell (Fig. 7-17). Mosaicism for numerical or structural abnormalities of chromosomes is a clinically important phenomenon (see Chapters 5 and 17), and somatic mutation is recognized as the major contributor to most types of cancer (see Chapter 15).


FIGURE 7-17 Schematic representation of a mutation occurring after conception, during mitotic cell divisions. Such a mutation can lead to a proportion of cells carrying the mutation—that is, to either somatic or germline mosaicism, depending on at what stage of embryonic or postnatal development the mutation occurred.

Mosaicism can affect any cells or tissue within a developing embryo or at any point after conception to adulthood, and it can be a diagnostic dilemma to determine just how widespread the mosaic pattern is. For example, the population of cells that carry a mutation in a mosaic pregnancy might be found only in extraembryonic tissue and not in the embryo proper (confined placental mosaicism; see Chapter 17), might be present in some tissues of the embryo but not in the gametes (pure somatic mosaicism), might be restricted to the gamete lineage only and nowhere else (pure germline mosaicism), or might be present in both somatic lineages and the germline—all depending on whether the mutation occurred before or after the separation of the inner cell mass, the germline cells, and the somatic cells during embryogenesis (see Chapter 17). Because there are approximately 30 mitotic divisions in the cells of the germline before meiosis in the female and several hundred in the male (see Chapter 2), there is ample opportunity for mutations to occur in germline cells after the separation from somatic cells, resulting in pure gonadal mosaicism.

Determining whether mosaicism for a mutation is present only in the germline or only in somatic tissues may be difficult because failure to find a mutation in a subset of cells from a readily accessible somatic tissue (e.g., peripheral white blood cells, skin, or buccal cells) does not ensure that the mutation is not present elsewhere in the body, including the germline.

Segmental Mosaicism

A mutation affecting morphogenesis and occurring during embryonic development might be manifested as a segmental or patchy abnormality, depending on the stage at which the mutation occurred and the lineage of the somatic cell in which it originated. For example, neurofibromatosis 1 (NF1) (Case 34) is sometimes segmental, affecting only one part of the body. Segmental NF1 is caused by somatic mosaicism for a mutation that occurred after conception. Although the parents of such a patient would be unaffected and considered not at risk for transmitting the mutant gene, a patient with segmental NF1 could be at risk for having an affected child, whose phenotype would be typical for NF1, that is, not segmental. Whether the patient is at risk for transmitting the defect will depend on whether the mutation occurred before separation of germline cells from the somatic cell line that carries the mutation.

Germline Mosaicism

In pedigrees with germline mosaicism, unaffected individuals with no evidence of a disease-causing mutation in their genome (as evidenced by the failure to find the mutation in DNA extracted from their peripheral white blood cells) may still be at risk for having more than one child who inherited the mutation from them (Fig. 7-18). The existence of germline mosaicism means that geneticists and genetic counselors must be aware of the potential inaccuracy of assuming that normal examination results and normal gene test results of the parents of a child with an autosomal dominant or X-linked phenotype means the child must be a new mutation. The impact of this possibility on risk assessment will be discussed further in Chapter 16.


FIGURE 7-18 Pedigrees demonstrating two affected siblings with the autosomal dominant disorder Marfan syndrome (Family A) and the X-linked condition Becker muscular dystrophy (Family B). In Family A, the affected children have the same point mutation inherited from their father, who is unaffected and does not carry the mutation in DNA from examined somatic tissues. He must have been a mosaic for the FBN1 mutation in his germline. In Family B, the affected children have the same point mutation inherited from their mother who is unaffected and does not carry the mutation in DNA from examined somatic tissues. She must have been a mosaic for the DMD mutation in her germline.

Parent-of-Origin Effects on Inheritance Patterns

Unusual Inheritance Patterns due to Genomic Imprinting

According to Mendel's laws of heredity, a mutant allele of an autosomal gene is equally likely to be transmitted from a parent of either sex to an offspring of either sex; similarly, a female is equally likely to transmit a mutated X-linked gene to a child of either sex. Originally, little attention was paid to whether the sex of the parent had any effect on the expression of the genes each parent transmits. As discussed in Chapter 6, we now know, however, that in some genetic disorders, such as Prader-Willi syndrome (Case 38) and Angelman syndrome, the expression of the disease phenotype depends on whether the mutant allele has been inherited from the father or from the mother, a phenomenon known as genomic imprinting. The hallmark of genomic imprinting is that the sex of the parent who transmits the abnormality determines whether there is expression of the disorder in a child. This is very different from sex-limited inheritance (described earlier in this chapter), in which expression of the disease depends on the sex of the child who inherits the abnormality.

Imprinting can cause unusual inheritance patterns in pedigrees, in that a disorder can appear to be inherited in a dominant manner when transmitted from one parent, but not the other. For example, the hereditary paragangliomas (PGLs) are a group of autosomal dominant disorders in which multiple tumors develop in sympathetic and parasympathetic ganglia of the autonomic nervous system. Patients with paraganglioma can also develop a catecholamine-producing tumor known as a pheochromocytoma, either in the adrenal medulla or in sympathetic ganglia along the vertebral column. A pedigree of one type of PGL family is shown in Figure 7-19. The striking observation is that, although both males and females can be affected, this is only if they inherited the mutation from their father and not from their mother. A male heterozygote who has inherited his mutation from his mother will remain unaffected throughout life but is still at a 50% risk for transmitting the mutation to each of his children, who are then at high risk for developing the disease.


FIGURE 7-19 Pedigree of a family with paraganglioma syndrome 1 caused by a mutation in the SDHD gene. Individuals II-1, II-2, II-4, III-2, III-3, III-9, III-10, IV-6, IV-7, IV-11, and IV-14 each inherited the mutation from their mothers but are unaffected. However, when the males in this group pass on the mutation, those children can be affected. In addition to the imprinting, the family also demonstrates the effect of reduced and age-dependent penetrance in the children (III-6, IV-10, IV-17) of heterozygous fathers. The + and − symbols refer to the presence or absence of the SDHD mutation in this family.

Dynamic Mutations: Unstable Repeat Expansions

In all of the types of inheritance presented thus far in this chapter, the responsible mutation, once it occurs, is stable when it is transmitted from one generation to the next; that is, all affected members of a family share the identical inherited mutation. In contrast, an entirely different class of genetic disease has been recognized, diseases due to dynamic mutations that change from generation to generation (see Chapter 4). These conditions are characterized by an unstable expansion within the affected gene of a segment of DNA consisting of repeating units of three or more nucleotides that occur in tandem. Many such repeat units consist of three nucleotides, such as CAG or CCG, and the repeat will therefore be CAGCAGCAGCAG or CCGCCGCCG CCG. In general, genes associated with these diseases all have wild-type alleles that are polymorphic; that is, there is a variable number of repeat units in the normal population, as we saw in Chapter 4. As the gene is passed from generation to generation, however, the number of repeats can increase and undergo expansion, far beyond the normal polymorphic range, leading to abnormalities in gene expression and function. The discovery of this unusual group of conditions has dispelled the orthodox notions of germline stability and provided a biological basis for peculiarities of familial transmission, discussed in the next section, that previously had no known mechanistic explanation.

More than a dozen diseases are known to result from unstable repeat expansions of this type. All of these conditions are primarily neurological. Here, we will review the inheritance patterns of two different unstable expansion diseases that illustrate the effects that different dynamic mutations can have on patterns of inheritance. A more complete description of the pathogenetic mechanisms of unstable repeat disorders is given in Chapter 12.

Polyglutamine Disorders

Several different neurological diseases share the property that the protein encoded by the gene mutated in each condition is characterized by a variable string of consecutive glutamine residues, the codon for which is the trinucleotide CAG. These so-called polyglutamine disorders result when an expansion of the CAG repeat leads to a protein with more glutamines than is compatible with normal function. Huntington disease (HD) is a well-known disorder that illustrates many of the common genetic features of the polyglutamine disorders caused by expansion of an unstable repeat (Case 24). The neuropathology is dominated by degeneration of the striatum and the cortex. Patients first present clinically in midlife and manifest a characteristic phenotype of motor abnormalities (chorea, dystonia), personality changes, a gradual loss of cognition, and ultimately death.

For a long time, HD was thought to be a typical autosomal dominant condition with age-dependent penetrance. The disease is transmitted from generation to generation with a 50% risk to each offspring, and heterozygous and homozygous patients carrying the mutation have very similar phenotypes, although homozygotes may have a more rapid course of their disease. There are, however, obvious peculiarities in its inheritance that cannot be explained by simple autosomal dominant inheritance. First, the disease appears to develop at an earlier and earlier age as it is transmitted through the pedigree, a phenomenon referred to as anticipation. Second, anticipation seems to occur only when the mutant allele is transmitted by an affected father and not by an affected mother, a situation known as parental transmission bias.

The peculiarities of inheritance of HD are now readily explained by the discovery that the mutation is composed of an abnormally long CAG expansion in the coding region of the HD gene. Normal individuals carry alleles with between 9 and 35 CAG repeats in their HD gene, with the average being 18 or 19. Individuals affected with HD, however, have 40 or more repeats, with the average being around 46. Repeat numbers in the range of 40 to 50 usually result in disease later in life, which explains the age-dependent penetrance that is a hallmark of this condition. A borderline repeat number of 36 to 39, although usually associated with HD, can be found in a few individuals who show no signs of the disease even at a fairly advanced age. The age of onset varies with how many CAG repeats are present (Fig. 7-20).


FIGURE 7-20 Graph correlating approximate age of onset of Huntington disease with the number of CAG repeats found in the HD gene. The solid line is the average age of onset, and the shaded area shows the range of age of onset for any given number of repeats. SeeSources & Acknowledgments.

How, then, does an individual come to have an expanded CAG repeat in his or her HD gene? First, he or she may inherit it from a parent who already has an expanded repeat beyond the normal range but has not yet developed the disease. Second, he or she may inherit an expanded repeat from a parent with repeat length of 35 to 40, which may or may not cause disease in the parent's lifetime but may expand on transmission, resulting in earlier-onset disease in later generations (and thus explaining anticipation). For example, in the pedigree shown in Figure 7-21, individual I-1, now deceased, was diagnosed with HD at the age of 64 years and was heterozygous for an expanded allele with 37 CAG repeats and a normal, stable allele with 25 repeats. Four of his children inherited the unstable allele, with CAG repeat lengths ranging from 42 to more than 100 repeats. Finally, unaffected individuals may carry alleles with repeat lengths at the upper limit of the normal range (29 to 35 CAG repeats) that can expand during meiosis to 40 or more repeats. CAG repeat alleles at the upper limits of normal that do not cause disease but are capable of expanding into the disease-causing range are known as premutations.


FIGURE 7-21 Pedigree of family with Huntington disease. Shown beneath the pedigree is a Southern blot analysis for CAG repeat expansions in the HD gene. In addition to a normal allele containing 25 CAG repeats, individual I-1 and his children, II-1, II-2, II-4, and II-5, are all heterozygous for expanded alleles, each containing a different number of CAG repeats. The repeat number is indicated below each individual. II-2, II-4, and II-5 are all affected; individual II-1 is unaffected at the age of 50 years but will develop the disease later in life. SeeSources & Acknowledgments.

Expansion in HD shows a paternal transmission bias and occurs most frequently during male gametogenesis, which is why the severe early-onset juvenile form of the disease, seen with the largest expansions (70 to 121 repeats), is always paternally inherited.

Fragile X Syndrome

The fragile X syndrome (Case 17) is the most common heritable form of moderate intellectual disability, one of many conditions now considered to be among the autism spectrum disorders. The name fragile X refers to a cytogenetic marker on the X chromosome at Xq27.3, a so-called fragile site induced in cultured cells in which the chromatin fails to condense properly during mitosis. The syndrome is inherited as an X-linked disorder with penetrance in females in the 50% to 60% range. The fragile X syndrome has a frequency of 1 in 3000 to 4000 male births and is so common that it requires consideration in the differential diagnosis of intellectual disability or autism in both males and females. Testing for the fragile X syndrome is among the most frequent indications for genome analysis, genetic counseling, and prenatal diagnosis.

Like HD, fragile X syndrome is caused by an unstable repeat expansion. However, in this case, a massive expansion of a different triplet repeat, CGG, occurs in the 5′ untranslated region of a gene called FMR1(Fig. 7-22). The normal number of repeats is up to 55, whereas more than 200 (and even up to several thousand) repeats are found in patients with the “full” fragile X syndrome mutation. The syndrome is due to a lack of expression of the FMR1 gene and failure to produce the encoded protein. The expanded repeat leads to excessive methylation of cytosines in the promoter of FMR1; as discussed in Chapter 3, DNA methylation at CpG islands prevents normal promoter function and leads to gene silencing.


FIGURE 7-22 Southern blot DNA from the members of a family in which fragile X syndrome is segregating. In the family shown at the top, DNA samples were digested either with the endonuclease EcoRI alone (E) or with the combination of EcoRI and BssH2 (B), an endonuclease that will not cut when the cytosines in its recognition sequence are methylated. EcoRI digestion normally yields a 5.2-kb fragment containing the region of the repeat, but the size of the fragment increases proportionately to the expansion of the triplet repeat. Digestion with BssH2 along with EcoRI (E/B) will reduce the 5.2-kb fragment generated by EcoRI to a 2.8-kb fragment containing the repeats if the CGG repeats are unmethylated, as is the case on the active X chromosome in a female, or if the repeats are not expanded into the full mutation range (>200 repeats). BssH2 cannot cut the 5.2-kb fragment coming from an inactive X or a fully expanded FMR1 allele. The affected individual has a large EcoRI fragment, much greater than 5.2 kb, that contains the expanded CGG repeat and is resistant to BssH2 digestion because it is mostly methylated. His mother has two fragments after EcoRI digestion, one normal in size and the other a few hundred base pairs larger, indicating she is a premutation carrier, as is her mother, the proband's grandmother. Upon double digestion, two fragments are seen, the normal at 2.8 kb and a premutation allele that is a few hundred base pairs larger. The proband has two uncles, one (shown in light blue) who appears mildly affected and has an expanded allele (based on EcoRI digestion) that is only partially methylated (based on BssH2 digestion). The other uncle is a normal male with a normal sized, unmethylated allele. SeeSources & Acknowledgments.

Triplet repeat numbers between 56 and 200 constitute an intermediate premutation stage of the fragile X syndrome. Expansions in this range are unstable when they are transmitted from mother to child and have an increasing tendency to undergo full expansion to more than 200 copies of the repeat during gametogenesis in the female (but almost never in the male), with the risk for expansion increasing dramatically with increasing premutation size (Fig. 7-23). The overall premutation frequency in females in the population is estimated to be greater than 1 in 200.


FIGURE 7-23 Frequency of expansion of a premutation triplet repeat in FMR1 to a full mutation in oogenesis as a function of the length of the premutation allele carried by a heterozygous female. The risk for fragile X syndrome to her sons is approximately half this frequency, because there is a 50% chance a son will inherit the expanded allele. The risk for fragile X syndrome to her daughters is approximately one-fourth this frequency, because there is a 50% chance a daughter would inherit the full mutation, and penetrance of the full mutation in a female is approximately 50%. SeeSources & Acknowledgments.

Similarities and Differences in Huntington Disease and Fragile X Pedigrees

A comparison of HD with the fragile X syndrome reveals some similarities but also many differences that illustrate many of the features of disorders due to dynamic mutations:

• Premutation expansions causing an increased risk for passing on full mutations are the rule in both of these disorders, and anticipation is commonly seen in both.

• However, the number of repeats in premutation alleles in HD is 29 to 35, far less than the 55 to 200 repeats in fragile X syndrome premutations.

• Premutation carriers for fragile X syndrome are at risk for adult-onset ataxia (in males) and ovarian failure (in females). But premutation carriers in HD are, by definition, disease-free.

• The expansion of premutation alleles occurs primarily in the female germline in fragile X syndrome; in contrast, the largest expansions causing juvenile-onset HD occur in the male germline.

Maternal Inheritance of Disorders Caused by Mutations in the Mitochondrial Genome

All of the patterns of inheritance described thus far are explained by mutations in the nuclear genome, in either autosomal or X-linked genes. However, some pedigrees of inherited diseases that do not show patterns of typical mendelian inheritance are caused by mutations in the mitochondrial genome and manifest strictly maternal inheritance. Disorders caused by mutations in mitochondrial DNA (mtDNA) demonstrate a number of unusual features that result from the unique characteristics of mitochondrial biology and function.

As introduced in Chapter 2, not all the RNA and protein synthesized in a cell are encoded in the DNA of the nucleus; a small but important fraction is encoded by genes in mtDNA. The mitochondrial genome consists of 37 genes that encode 13 subunits of enzymes involved in oxidative phosphorylation, as well as ribosomal RNAs and transfer RNAs required for translating the transcripts of the mitochondria-encoded polypeptides. Because mitochondria are essential to the normal functioning of nearly all cells, disruption of energy production of mutations in mtDNA often results in severe disease, affecting many different tissues. Thus pleiotropy is the rule, not the exception, in mitochondrial disorders.

More than 100 different rearrangements and 100 different point mutations have been identified in mtDNA that can cause a range of human diseases, often involving the central nervous and musculoskeletal systems, such as myoclonic epilepsy with ragged-red fibers (Case 33). In this section, we will focus on the distinctive pattern of inheritance because of three unusual features of mitochondria: maternal inheritancereplicative segregation, and homoplasmy and heteroplasmy. The underlying mechanisms of mitochondrial disorders are discussed in more detail in Chapter 12.

Maternal Inheritance of mtDNA

The first defining characteristic of the genetics of mtDNA is its maternal inheritance. Sperm mitochondria are generally not present in the zygote, so that only the maternal mtDNA is transmitted to the next generation. Thus the children of a female who has a mtDNA mutation will inherit the mutation, whereas none of the offspring of a male carrying the same mutation will inherit the defective DNA. Pedigrees of such disorders are quite distinctive, as shown by the strictly maternal inheritance of a mtDNA mutation causing Leber hereditary optic neuropathy seen in Figure 7-24. Although maternal inheritance is the general expectation, at least one instance of paternal inheritance of mtDNA has occurred in a patient with a mitochondrial myopathy. Consequently, in patients with apparently sporadic mtDNA mutations, the rare occurrence of paternal mtDNA inheritance must be considered (see Box).


FIGURE 7-24 Pedigree of Leber hereditary optic neuropathy, a form of adult-onset blindness caused by a defect in mitochondrial DNA. Inheritance is only through the maternal lineage, in agreement with the known maternal inheritance of mitochondrial DNA. Note that no affected male transmits the disease.

Replicative Segregation

A second feature of the mitochondrial genome is the stochastic nature of segregation during mitosis and meiosis. At cell division, the multiple copies of mtDNA in each of the mitochondria in each cell replicate and sort randomly among newly synthesized mitochondria, in stark contrast to the highly predictable and programmed segregation of the 46 nuclear chromosomes. The mitochondria themselves, in turn, are then distributed randomly between the two daughter cells. This process is known as replicative segregation and can result in significant variability in manifestations of mitochondrial disorders among different tissues and/or patients.

Homoplasmy and Heteroplasmy

Finally, a distinctive feature of the genetics of mtDNA is seen when replicative segregation occurs in mitochondria containing both mutant and wild-type mitochondrial genomes. When a mutation first occurs in the mtDNA, it is present in only one of the mtDNA molecules in a mitochondrion. With cell division, all the mtDNAs replicate, the mitochondria undergo fission, and the mutant and wild-type DNA are distributed randomly into daughter organelles, which—simply by chance—may contain different proportions of wild-type and mutant mitochondrial genomes. The cell, which now contains mitochondria containing different mixtures of normal and mutant mtDNAs, in turn distributes those mitochondria randomly to its daughter cells. Daughter cells may thus receive a mixture of mitochondria, some with and some without the mutation (a situation known as heteroplasmyFig. 7-25). Occasionally, a daughter cell may receive, again by chance, mitochondria that contain a pure population of normal mtDNA or a pure population of mutant mtDNA (a situation known as homoplasmy). Because the phenotypic expression of a mutation in mtDNA depends on the relative proportions of normal and mutant mtDNA in the cells making up different tissues, reduced penetrance and variable expression are typical features of mitochondrial disorders (Case 33).


FIGURE 7-25 Replicative segregation of a heteroplasmic mitochondrial mutation. Random partitioning of mutant and wild-type mitochondria through multiple rounds of mitosis produces a collection of daughter cells with wide variation in the proportion of mutant and wild-type mitochondria carried by each cell. Cell and tissue dysfunction results when the fraction of mitochondria that are carrying a mutation exceeds a threshold level. mtDNA, Mitochondrial DNA; N, nucleus.

Maternal inheritance in the presence of heteroplasmy in the mother is associated with additional features of mtDNA genetics that are of medical significance. First, the number of mtDNA molecules within developing oocytes is reduced before being subsequently amplified to the huge total seen in mature oocytes. This restriction and subsequent amplification of mtDNA during oogenesis is termed the mitochondrial genetic bottleneck. Consequently, the variability in the proportion of mutant mtDNA molecules seen in the offspring of a mother with heteroplasmy for a mtDNA mutation arises, at least in part, from the sampling of a reduced subset of the mtDNAs after the mitochondrial bottleneck that occurs in oogenesis. As might be expected, mothers with a high proportion of mutant mtDNA molecules are more likely to produce eggs with a higher proportion of mutant mtDNA and therefore are more likely to have clinically affected offspring than are mothers with a lower proportion.

Characteristics of Mitochondrial Inheritance

• All children of females homoplasmic for a mutation will inherit the mutation; the children of males carrying a similar mutation almost always will not.

• Females heteroplasmic for point mutations and duplications will pass them on to all of their children. However, the fraction of mutant mitochondria in the offspring, and therefore the risk and severity of disease, can vary considerably, depending on the fraction of mutant mitochondria in their mother as well as on random chance operating on small numbers of mitochondria per cell at the oocyte bottleneck. Heteroplasmic deletions are generally not heritable.

• The fraction of mutant mitochondria in different tissues of an individual heteroplasmic for a mutation can vary tremendously, thereby causing a spectrum of disease among the members of a family in which there is heteroplasmy for a mitochondrial mutation. Pleiotropy and variable expressivity in different affected family members are also frequent.

Correlating Genotype and Phenotype

An important component of medical genetics is identifying and characterizing the genotypes responsible for particular disease phenotypes. In doing so, it is important not to adhere to an overly simplistic view that each disease phenotype is caused uniquely by one particular mutation in a specific gene or that mutations in a particular gene always cause the same phenotype. In fact, there is often substantial heterogeneity in the complex relationship(s) among disease phenotypes, the genes that are mutated in those diseases, and the nature of the mutations found in those genes. Three main types of heterogeneity are distinguished, as will be illustrated in detail in Chapters 11 and 12. Here, we introduce them and outline their distinguishing features.

• Allelic heterogeneity, in which different mutations in a gene may produce the same phenotype

• Locus heterogeneity, in which mutations in different genes may cause the same phenotype

• Clinical or phenotypic heterogeneity, in which different mutations in a gene may result in different phenotypes.

Allelic Heterogeneity

Many loci possess more than one mutant allele; in fact, at a given locus, there may be several or many mutations in the population. Allelic heterogeneity may be responsible for differences in the severity or degree of pleiotropy demonstrated for a particular condition. As one example, more than 1000 different mutations have been found worldwide in the cystic fibrosis transmembrane conductance regulator gene (CFTR) among patients with CF (Case 12). Sometimes these different mutations result in clinically indistinguishable disorders. In other cases, different mutant alleles at the same locus produce a similar phenotype but along a continuum of severity. In autosomal recessive disorders, in particular, the fact that many patients are compound heterozygotes for two different alleles further adds to phenotypic variability of a disorder. For example, homozygotes or compound heterozygotes for many CFTR mutations have classic CF with pancreatic insufficiency, severe progressive lung disease, and congenital absence of the vas deferens in males, whereas other patients with combinations of other mutant alleles may have lung disease but normal pancreatic function, and still others will have only the abnormality of the male reproductive tract.

Allelic heterogeneity may also be manifest in the pattern of inheritance demonstrated for a particular condition. For example, in retinitis pigmentosa, a common cause of hereditary visual impairment due to photoreceptor degeneration, some mutations in the ORP1 gene, encoding an oxygen-regulated photoreceptor protein, cause an autosomal recessive form of the disease, whereas others in the same gene result in an autosomal dominant form.

Locus Heterogeneity

Locus heterogeneity describes the situation in which clinically similar and even indistinguishable disorders may arise from mutations in different loci in different patients. For some phenotypes, pedigree analysis alone has been sufficient to demonstrate locus heterogeneity. Taking retinitis pigmentosa again as an example, it was recognized many years ago that the disease occurs in both autosomal and X-linked forms. Now, pedigree analysis combined with gene mapping has demonstrated that this single clinical entity can be caused by mutations in at least 56 different genes, 54 of which are autosomal and 2 of which are X-linked!

Clinical Heterogeneity

Different mutations in the same gene may produce very dissimilar phenotypes in different families, a phenomenon known as clinical or phenotypic heterogeneity. This situation occurs with mutations in the LMNA gene, which encodes a nuclear membrane protein. Different LMNA mutations have been associated with at least a half dozen phenotypically distinct disorders, including a form of muscular dystrophy, one form of hereditary dilated cardiomyopathy, one form of the Charcot-Marie-Tooth peripheral neuropathy, a disorder of adipose tissue called lipodystrophy, and the premature aging syndrome known as Hutchinson-Gilford progeria.

Importance of the Family History in Medical Practice

Among medical specialties, medical genetics is distinctive in that it focuses not only on the patient but also on the entire family. A comprehensive family history is an important first step in the analysis of any disorder, whether or not the disorder is known to be genetic. As the late Barton Childs stated succinctly: “to fail to take a good family history is bad medicine.” Despite the sophisticated cytogenetic, molecular, and genome testing now available to geneticists, an accurate family history (including the family pedigree) still remains a fundamental tool for all physicians and genetic counselors to use for determining the pattern of inheritance of a disorder in the family, forming a differential diagnosis, determining what genetic testing might be needed, and designing an individualized management and treatment plan for their patients. Furthermore, recognizing a familial component to a medical disorder allows the risk in other family members to be estimated so that proper management, prevention, and counseling can be offered to the patient and the family, as we will discuss in many of the chapters to follow.

General References

Bennett RL, French KS, Resta RG, Doyle DL. Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. J Genet Counsel. 2008;17:424–433.

Online Mendelian Inheritance in Man, OMIM, Baltimore, Johns Hopkins University. Updated online at:

Rimoin DL, Pyeritz RE, Korf BR. Emery and Rimoin's essential medical genetics. Academic Press: Oxford; 2013.

Scriver CR, Beaudet AL, Sly WS, et al. The metabolic and molecular bases of inherited disease. ed 8. McGraw-Hill: New York; 2000 [Updated online version available at]


1. Cathy is pregnant for the second time. Her first child, Donald, has cystic fibrosis (CF). Cathy has two brothers, Charles and Colin, and a sister, Cindy. Colin and Cindy are unmarried. Charles is married to an unrelated woman, Carolyn, and has a 2-year-old daughter, Debbie. Cathy's parents are Bob and Betty. Betty's sister Barbara is the mother of Cathy's husband, Calvin, who is 25. There is no previous family history of CF.

a. Sketch the pedigree, using standard symbols.

b. What is the pattern of transmission of CF, and what is the risk for CF for Cathy's next child?

c. Which people in this pedigree are obligate heterozygotes?

2. George and Grace, who have normal hearing, have eight children; two of their five daughters and two of their three sons are congenitally deaf. Another couple, Harry and Helen, both with normal hearing, also have eight children; two of their six daughters and one of their two sons are deaf. A third couple, Gilbert and Gisele, who are congenitally deaf, have four children, also deaf. Their daughter Hedy marries Horace, a deaf son of George and Grace, and Hedy and Horace in turn have four deaf children. Their eldest son Isaac marries Ingrid, a daughter of Harry and Helen; although both Isaac and Ingrid are deaf, their six sons all have normal hearing. Sketch the pedigree and answer the following questions. (Hint: How many different types of congenital deafness are segregating in this pedigree?)

a. State the probable genotypes of the children in the last generation.

b. Why are all the children of Gilbert and Gisele and of Hedy and Horace deaf?

3. Consider the following situations:

a. Retinitis pigmentosa occurs in X-linked and autosomal forms.

b. Two parents each have a typical case of familial hypercholesterolemia diagnosed on the basis of hypercholesterolemia, arcus corneae, tendinous xanthomas, and demonstrated deficiency of low-density lipoprotein (LDL) receptors, together with a family history of the disorder; they have a child who has a very high plasma cholesterol level at birth and within a few years develops xanthomas and generalized atherosclerosis.

c. A couple with normal vision, from an isolated community, have a child with autosomal recessive gyrate atrophy of the retina. The child grows up, marries another member (with normal vision) of the same community, and has a child with the same eye disorder.

d. A child has severe neurofibromatosis 1 (NF1). Her father is phenotypically normal; her mother seems clinically normal but has several large café au lait spots and areas of hypopigmentation, and slit-lamp examination shows that she has a few Lisch nodules (hamartomatous growths on the iris).

e. Parents of normal stature have a child with achondroplasia.

f. An adult male with myotonic dystrophy has cataracts, frontal balding, and hypogonadism, in addition to myotonia.

g. A man with vitamin D–resistant rickets transmits the condition to all his daughters, who have a milder form of the disease than their father has; none of his sons is affected. The daughters have approximately equal numbers of unaffected sons, affected sons, unaffected daughters, and affected daughters, the affected sons being more severely affected than their affected sisters.

h. A boy has progressive muscular dystrophy with onset in early childhood and is wheelchair-bound by the age of 12 years. An unrelated man also has progressive muscular dystrophy but is still ambulant at the age of 30 years. Molecular analysis shows that both patients have large deletions in the dystrophin gene, which encodes the protein that is deficient or defective in the Duchenne and Becker types of muscular dystrophy.

i. A patient with a recessive disorder is found to have inherited both copies of one chromosome from the same parent and no representative of that chromosome from the other parent.

j. A child with maple syrup urine disease is born to parents who are first cousins.

Which of the concepts listed here are illustrated by situations a to j?

• Variable expressivity

• Uniparental disomy

• Consanguinity

• Inbreeding

• X-linked dominant inheritance

• New mutation

• Allelic heterogeneity

• Locus heterogeneity

• Autosomal incompletely dominant trait

• Pleiotropy

4. Don and his maternal grandfather Barry both have hemophilia A. Don's partner Diane is his maternal aunt's daughter. Don and Diane have one son, Edward, and two daughters, Elise and Emily, all of whom have hemophilia A. They also have an unaffected daughter, Enid.

a. Draw the pedigree.

b. Why are Elise and Emily affected?

c. What is the probability that a son of Elise would be hemophilic? What is the probability that her daughter would be hemophilic?

d. What is the probability that a son of Enid would be hemophilic? A daughter?

5. A boy is born with a number of malformations but does not have a recognized syndrome. The parents are unrelated, and there is no family history of a similar condition. Which of the following conditions could explain this situation? Which are unlikely? Why?

a. Autosomal dominant inheritance with new mutation

b. Autosomal dominant inheritance with reduced penetrance

c. Autosomal dominant inheritance with variable expressivity

d. Autosomal recessive inheritance

e. X-linked recessive inheritance

f. Autosomal dominant inheritance, misattributed paternity

g. Maternal ingestion of a teratogenic drug at a sensitive stage of embryonic development

6. A couple has a child with NF1. Both parents are clinically normal, and neither of their families shows a positive family history.

a. What is the probable explanation for NF1 in their child?

b. What is the risk for recurrence in other children of this couple?

c. If the husband has another child by a different mother, what would the risk for NF1 be?

d. What is the risk that any offspring of the affected child will also have NF1?

7. The consultand (arrow) wants to know her risk for having a child with a birth defect before starting her family because she and her husband are related (see pedigree). The family history reveals no known recessive disease. What is the chance that her child could be homozygous for a mutation for a recessive disorder carried by one of the two common ancestors in generation I (the coefficient of inbreeding)? (Hint: The mutation could be on either of the two chromosomes in either of the two common ancestors.)


8. Given the pedigree below, what is/are the most likely inheritance pattern(s); possible but less likely inheritance pattern(s); incompatible inheritance pattern(s)? Patterns are autosomal recessive, autosomal dominant, X-linked recessive, X-linked dominant, mitochondrial. Justify your choices.


9. When a child is affected with an autosomal recessive condition, the assumption is that both parents are heterozygous carriers for the condition. Yet, new mutations occur all the time during the generation of gametes (see Chapter 4). Might not an individual have two mutant alleles for an autosomal recessive condition by virtue of inheriting one mutant allele from a carrier parent, whereas the other mutant allele arose de novo in a gamete that came from a parent who was not a carrier? Consider a child with cystic fibrosis. Calculate the odds (ratio of the probabilities) that both parents are carriers versus the probability that only the mother is a carrier and the sperm brought in a de novo mutation. Assume an average mutation rate of approximately 1 ×10−6 per male gamete per generation.

*The terms genetic and congenital are frequently confused. Keep in mind that a genetic disorder is one that is determined by variation in genes, whereas a congenital disorder is simply one that is present at birth and may or may not have a genetic basis.