An autosomal dominant trait is one that manifests in the heterozygous state, that is, in a person possessing both an abnormal or mutant allele and the normal allele. It is often possible to trace a dominantly inherited trait or disorder through many generations of a family (Figure 7.2). In South Africa the vast majority of cases of porphyria variegata can be traced back to one couple in the late seventeenth century. This is a metabolic disorder characterized by skin blistering as a result of increased sensitivity to sunlight (Figure 7.3), and the excretion of urine that becomes ‘port wine’ colored on standing as a result of the presence of porphyrins (p. 179). This pattern of inheritance is sometimes referred to as ‘vertical’ transmission and is confirmed when male–male (i.e., father to son) transmission is observed.

FIGURE 7.2 Family tree of an autosomal dominant trait. Note the presence of male-to-male transmission.

FIGURE 7.3 Blistering skin lesions on the hand in porphyria variegata.

Genetic Risks

Each gamete from an individual with a dominant trait or disorder will contain either the normal allele or the mutant allele. If we represent the dominant mutant allele as ‘D’ and the normal allele as ‘d’, then the possible combinations of the gametes is seen in Figure 7.4. Any child born to a person affected with a dominant trait or disorder has a 1 in 2 (50%) chance of inheriting it and being similarly affected. These diagrams are often used in the genetic clinic to explain segregation to patients and are more user-friendly than a Punnett square (see Figs. 1.3 and 8.1).

FIGURE 7.4 Segregation of alleles in autosomal dominant inheritance. D represents the mutated allele, whereas d represents the normal allele.

Pleiotropy

Autosomal dominant traits may involve only one organ or part of the body, for example the eye in congenital cataracts. It is common, however, for autosomal dominant disorders to manifest in different systems of the body in a variety of ways. This is pleiotropy—a single gene that may give rise to two or more apparently unrelated effects. In tuberous sclerosis affected individuals can present with a range of problems including learning difficulties, epilepsy, a facial rash known as adenoma sebaceum (histologically composed of blood vessels and fibrous tissue known as angiokeratoma) or subungual fibromas (Figure 7.5); some affected individuals have all features, whereas others may have almost none. Some discoveries are challenging our conceptual understanding of the term pleiotropy on account of the remarkably diverse syndromes that can result from different mutations in the same gene—for example, the LMNA gene (which encodes lamin A/C) and the X-linked filamin A (FLNA) gene. Mutations in LMNA may cause Emery-Dreifuss muscular dystrophy, a form of limb girdle muscular dystrophy, a form of Charcot-Marie-Tooth disease (p. 305), dilated cardiomyopathy (p. 296) with conduction abnormality, Dunnigan-type familial partial lipodystrophy (Figure 7.6), mandibuloacral dysplasia, and a very rare condition that has always been a great curiosity—Hutchinson-Gilford progeria. These are due to heterozygous mutations, with the exception of the Charcot-Marie-Tooth disease and mandibuloacral dysplasia, which are recessive—affected individuals are therefore homozygous for LMNA mutations. Sometimes an individual with a mutation is entirely normal. Mutations in the filamin A gene have been implicated in the distinct, though overlapping, X-linked dominant dysmorphic conditions oto-palato-digital syndrome, Melnick-Needles syndrome and frontometaphyseal dysplasia. However, it could not have been foreseen that a form of X-linked dominant epilepsy in women, called periventricular nodular heterotopia, is also due to mutations in this gene.

FIGURE 7.5 The facial rash (A) of angiokeratoma (adenoma sebaceum) in a male with tuberous sclerosis, and a typical subungual fibroma of the nail bed (B).

FIGURE 7.6 Dunnigan-type familial partial lipodystrophy due to a mutation in the lamin A/C gene. The patient lacks adipose tissue, especially in the distal limbs. A wide variety of clinical phenotypes is associated with mutations in this one gene.

Variable Expressivity

The clinical features in autosomal dominant disorders can show striking variation from person to person, even in the same family. This difference between individuals is referred to as variable expressivity. In autosomal dominant polycystic kidney disease, for example, some affected individuals develop renal failure in early adulthood whereas others have just a few renal cysts that do not affect renal function significantly.

Reduced Penetrance

In some individuals heterozygous for gene mutations giving rise to certain autosomal dominant disorders, there may be no abnormal clinical features, representing so-called reduced penetrance or what is commonly referred to in lay terms as ‘skipping a generation’. Reduced penetrance is thought to be the result of the modifying effects of other genes, as well as interaction of the gene with environmental factors. An individual who has no features of a disorder despite being heterozygous for a particular gene mutation is said to represent non-penetrance.

Reduced penetrance and variable expressivity, together with the pleiotropic effects of a mutant allele, all need to be taken into account when trying to interpret family history information for disorders that follow autosomal dominant inheritance. A good example of a very variable condition for which non-penetrance is frequently seen is Treacher-Collins syndrome. In its most obvious manifestation the facial features are unmistakable (Figure 7.7). However, the mother of the child illustrated is also known to harbor the gene (TCOF1) mutation as she has a number of close relatives with the same condition.

FIGURE 7.7 The baby in this picture has Treacher-Collins syndrome, resulting from a mutation in TCOF1. The mandible is small, the palpebral fissures slant downward, there is usually a defect (coloboma) of the lower eyelid, the ears may show microtia, and hearing impairment is common. The condition follows autosomal dominant inheritance but is very variable—the baby’s mother also has the mutation but she shows no obvious signs of the condition.

In autosomal dominant disorders an affected person usually has an affected parent. However, this is not always the case and it is not unusual for a trait to appear in an individual when there is no family history of the disorder. A striking example is achondroplasia, a form of short-limbed dwarfism (pp. 93–94), in which the parents usually have normal stature. The sudden unexpected appearance of a condition arising as a result of a mistake occurring in the transmission of a gene is called a new mutation. The dominant mode of inheritance of achondroplasia could be confirmed only by the observation that the offspring of persons with achondroplasia had a 50% chance of having achondroplasia. In less dramatic conditions other explanations for the ‘sudden’ appearance of a disorder must be considered. This includes non-penetrance and variable expression, as mentioned in the previous section. However, the astute clinician also needs to be aware that the family relationships may not be as stated—i.e., there may be undisclosed non-paternity (p. 342) (or, occasionally, non-maternity).

New dominant mutations, in certain instances, have been associated with an increased age of the father. Traditionally, this is believed to be a consequence of the large number of mitotic divisions that male gamete stem cells undergo during a man’s reproductive lifetime (p. 41). However, this may well be a simplistic view. In relation to mutations in FGFR2 (craniosynostosis syndromes), ground-breaking work by Wilkie’s group in Oxford demonstrated that causative gain-of-function mutations confer a selective advantage to spermatogonial stem cells, so that mutated cell lines accumulate in the testis.

Co-Dominance

Co-dominance is the term used for two allelic traits that are both expressed in the heterozygous state. In persons with blood group AB it is possible to demonstrate both A and B blood group substances on the red blood cells, so the A and B blood groups are therefore co-dominant (p. 205).

Homozygosity for Autosomal Dominant Traits

The rarity of most autosomal dominant disorders and diseases means that they usually occur only in the heterozygous state. There are, however, a few reports of children born to couples where both parents are heterozygous for a dominantly inherited disorder. Offspring of such couples are, therefore, at risk of being homozygous. In some instances, affected individuals appear either to be more severely affected, as has been reported with achondroplasia, or to have an earlier age of onset, as in familial hypercholesterolemia (p. 175). The heterozygote with a phenotype intermediate between the homozygotes for the normal and mutant alleles is consistent with a haploinsufficiency loss-of-function mutation (p. 26).

Conversely, with other dominantly inherited disorders, homozygous individuals are not more severely affected than heterozygotes—e.g., Huntington disease (p. 293) and myotonic dystrophy (p. 295).

Autosomal Recessive Inheritance

Recessive traits and disorders are manifest only when the mutant allele is present in a double dose (i.e., homozygosity). Individuals heterozygous for such mutant alleles show no features of the disorder and are perfectly healthy; they are described as carriers. The family tree for recessive traits (Figure 7.8) differs markedly from that seen in autosomal dominant traits. It is not possible to trace an autosomal recessive trait or disorder through the family, as all the affected individuals in a family are usually in a single sibship (i.e., brothers and sisters). This is sometimes referred to as ‘horizontal’ transmission, but this is an inappropriate and misleading term.

FIGURE 7.8 Family tree of an autosomal recessive trait.

Consanguinity

Enquiry into the family history of individuals affected with rare recessive traits or disorders might reveal that their parents are related (i.e., consanguineous). The rarer a recessive trait or disorder, the greater the frequency of consanguinity among the parents of affected individuals. In cystic fibrosis, the most common ‘serious’ autosomal recessive disorder in western Europeans (p. 1), the frequency of parental consanguinity is only slightly greater than that seen in the general population. By contrast, in alkaptonuria, one of the original inborn errors of metabolism (p. 171), which is an exceedingly rare recessive disorder, Bateson and Garrod, in their original description of the disorder, observed that one-quarter or more of the parents were first cousins. They reasoned that rare alleles for disorders such as alkaptonuria are more likely to ‘meet up’ in the offspring of cousins than in the offspring of parents who are unrelated. In large inbred kindreds an autosomal recessive condition may be present in more than one branch of the family.

Mutational Heterogeneity

Heterogeneity can also occur at the allelic level. In the majority of single-gene disorders (e.g., β-thalassemia) a large number of different mutations have been identified as being responsible (p. 160). There are individuals who have two different mutations at the same locus and are known as compound heterozygotes, constituting what is known as allelic or mutational heterogeneity. Most individuals affected with an autosomal recessive disorder are probably compound heterozygotes rather than true homozygotes, unless their parents are related, when they are likely to be homozygous for the same mutation by descent, having inherited the same mutation from a common ancestor.

Sex-Linked Inheritance

Sex-linked inheritance refers to the pattern of inheritance shown by genes that are located on either of the sex chromosomes. Genes carried on the X chromosome are referred to as being X-linked, and those carried on the Y chromosome are referred to as exhibiting Y-linked or holandric inheritance.

X-Linked Recessive Inheritance

An X-linked recessive trait is one determined by a gene carried on the X chromosome and usually manifests only in males. A male with a mutant allele on his single X chromosome is said to be hemizygous for that allele. Diseases inherited in an X-linked manner are transmitted by healthy heterozygous female carriers to affected males, as well as by affected males to their obligate carrier daughters, with a consequent risk to male grandchildren through these daughters (Figure 7.11). This type of pedigree is sometimes said to show ‘diagonal’ or a ‘knight’s move’ pattern of transmission.

FIGURE 7.11 Family tree of an X-linked recessive trait in which affected males reproduce.

The mode of inheritance whereby only males are affected by a disease that is transmitted by normal females was appreciated by the Jews nearly 2000 years ago. They excused from circumcision the sons of all the sisters of a mother who had sons with the ‘bleeding disease’, in other words, hemophilia (p. 309). The sons of the father’s siblings were not excused. Queen Victoria was a carrier of hemophilia, and her carrier daughters, who were perfectly healthy, introduced the gene into the Russian and Spanish royal families. Fortunately for the British royal family, Queen Victoria’s son, Edward VII, did not inherit the gene and so could not transmit it to his descendants.

Genetic Risks

A male transmits his X chromosome to each of his daughters and his Y chromosome to each of his sons. If a male affected with hemophilia has children with a normal female, then all of his daughters will be obligate carriers but none of his sons will be affected (Figure 7.12). A male cannot transmit an X-linked trait to his son, with the very rare exception of uniparental heterodisomy (p. 121).

FIGURE 7.12 Segregation of alleles in X-linked recessive inheritance, relating to the offspring of an affected male. r represents the mutated allele.

For a carrier female of an X-linked recessive disorder having children with a normal male, each son has a 1 in 2 (50%) chance of being affected and each daughter has a 1 in 2 (50%) chance of being a carrier (Figure 7.13).

FIGURE 7.13 Segregation of alleles in X-linked recessive inheritance, relating to the offspring of a carrier female. r represents the mutated allele.

Some X-linked disorders are not compatible with survival to reproductive age and are not, therefore, transmitted by affected males. Duchenne muscular dystrophy is the commonest muscular dystrophy and is a severe disease (p. 307). The first sign is delayed walking followed by a waddling gait, difficulty in climbing stairs unaided, and a tendency to fall easily. By about the age of 10 years affected boys usually need to use a wheelchair. The muscle weakness progresses gradually and affected males ultimately become confined to bed and often die in their late teenage years or early 20s (Figure 7.14). Because affected boys do not usually survive to reproduce, the disease is transmitted by healthy female carriers (Figure 7.15), or may arise as a new mutation.