Autosomal dominant

Autosomal dominance is a pattern of inheritance involving a dominant allele that is carried on an autosome. Autosomal dominant diseases include Huntingdon’s Disease. As with all cases of autosomal inheritance, sex is irrelevant in the transmission of an autosomal dominant disease (i.e. males and females are equally likely to be affected). If an affected parent mates with an unaffected parent, then 50% of the offspring would be expected to inherit the disease. Not all autosomal dominant diseases show full penetrance and expressivity (although Huntingdon’s Disease invariably shows 100% penetrance).

Below is an example of a pedigree that shows an autosomal-dominant pattern of inheritance:

external image domped.gif
external image domped.gif

In a human pedigree where there is an autosomal-dominant pattern of inheritance, it should usually be assumed that an affected individual is heterozygous unless proved otherwise, for three reasons:

  • The disease is usually rare, with only about 1 in 10,000 individuals affected. To produce a homozygote, two affected heterozygotes would have to mate. This probability is 1 in 1,000,000 (= 1/10,000 x 1/10,000) and even then there is only a 1 in 4 chance of having a homozygous affected offspring. This means that the probability of an individual being homozygous for an autosomal dominant disorder is about 1 in 4,000,000. Affected individuals are therefore much likely to come from affected x normal matings.

  • In the extremely rare instances where two affected individuals have mated, the homozygous affected individuals are usually so severely affected they are not viable. The exceptions are autosomal dominant diseases caused by the somatic expansion of trinucleotide repeat sequences (e.g. Huntington's disease) which generally have late onset.

  • The mating of very closely related individuals, the most likely way for two affected individuals to know each other, is forbidden in our society.

With the understanding that almost all affected individuals are heterozygotes, and that in most cases a person with an autosomal dominant trait will mate with an individual is homozygous-recessive, there are four hallmarks of autosomal dominant inheritance.

  • Sex of the parent and of the child is irrelevant in the transmission of the disease.

  • Except for new mutations, which are rare in nature and extremely rare on examination pedigrees, and the complexities of incomplete penetrance, every affected individual has an affected biological parent. There is no skipping of generations.

  • The recurrence risk of each child of an affected parent is 1/2. Normal siblings of affected individuals do not transmit the trait to their offspring.

  • The defective product of the gene is usually a structural protein, not an enzyme. Structural proteins are usually defective when one of the allelic products is nonfunctional; enzymes usually require both allelic products to be nonfunctional to produce a mutant phenotype.

Autosomal dominant diseases, as is implied by the term 'disease', produce evolutionarily deleterious phenotypes. With this in mind it is curious that such traits are not eliminated from the gene pool by natural selection. There are multiple reasons why autosomal dominant diseases are maintained from generation to generation in spite of their negative effects, some of which are described below.

Variable expressivity: One example of variable expressivity is Marfan syndrome. Marfan syndrome is an autosomal dominant disease caused by a mutation in collagen formation. It affects about 1/60,000 live births. Symptoms of Marfan syndrome include skeletal, optical, and cardiovascular abnormalities. Skeletal abnormalities include arachnodactyly (long fingers and toes), extreme lengthening of the long bones, scoliosis, rib and sternum abnormalities, among others. Optical abnormalities almost always include ectopia lentis, a dislocation of the lens into the anterior chamber of the eye. Cardiovascular abnormalities may be numerous and include possible dissecting aneurysms, which are largely responsible for the shorter life span of Marfan syndrome patients as a group. Each patient may express all of the symptoms, or only a few. That is variable expressivity. Each patient with the mutant allele for Marfan syndrome expresses at least one of the symptoms, but the physician may have to look closely. Almost all are taller than average, but a lot of non-Marfan individuals are tall. Almost all have long fingers, but so do a lot of non-Marfan persons. Some may be very mildly affected and lead normal lives while others, more severely affected, have a shorter life expectancy. The disease is maintained in the population through recurrent mutations and the matings of less severely affected individuals with normal individuals. The extent of severity of affected does not affect the severity of expression in the next generation, that is, the offspring of mildly affected individuals range from mildly affected to severely affected, with equal probability.

Late onset of the disease: Some autosomal dominant diseases do not express themselves until later in life, well beyond the reproductive years. The individuals who will develop the disease have passed the mutant allele along to their offspring before they themselves know they are affected. In some cases even grandchildren are born before the affected grandparent shows the first signs of the disease. Huntington disease, sometimes called Huntington's Chorea because of the choreic movements expressed as the disease progresses, is a good example of a late onset disease. Age of onset varies from the teens to the late sixties, with a mean age of onset between ages 35 and 45. Nearly 100% of the individuals born with the defective allele will develop the disease by the time they are 70. The disease is progressive with death usually occurring between four and twenty-five years after the first symptoms develop. Emotional changes often are the first symptoms. At the gene level, it is caused by the expansion of an unstable trinucleotide repeat sequence, CAG, in the coding region of the gene. What is inherited at birth in Huntington disease is a gene with several repeats and the instability that allows somatic recombination and extension. Somatic mutations introduced by the expansion of trinucleotide repeat sequences do not have to occur in coding regions to produce a mutant allele. Other diseases, such as myotonic dystrophy, an autosomal dominant disease where expression is delayed, result from molecular defects at the gene level that are caused by the expansion of unstable trinucleotide sequences. (In the case of myotonic dystrophy the sequence is CTG.) However, this unstable sequence lies in a non-translated region of the gene. In both diseases the size of the inherited expansion correlates to the age of onset or the severity of disease, but is not absolutely predictable on an individual basis. One cannot sequence the gene and precisely predict the age of onset of Huntington disease.

High recurrent mutation rate: Achondroplasia is one of the major causes of dwarfism. Motor skills may not develop as quickly as their normal siblings, but intelligence is not reduced. It occurs in about 1/10,000 live births. Like many autosomal dominant diseases, individuals homozygous for the mutant allele do not survive to term. Almost 85% of the cases are the result of new mutations, where both parents have a normal phenotype. The mutation rate for achondroplasia may be as much as 10 times the "normal" mutation rate in humans. This high recurrent mutation is largely responsible for keeping the mutant gene in the population at its present rate. Several other autosomal dominant genetic diseases have high recurrent mutation rates but achondroplasia is probably the best known.

Incomplete pentrance: Incomplete penetrance should never be confused with variable expressivity. In diseases with variable expressivity the patient always expresses some of the symptoms of the disease and varies from very mildly affected to very severely affected. In autosomal dominant diseases with incomplete penetrance, the person either expresses the disease phenotype or he/she doesn't. Incomplete penetrance and variable expressivity are phenomena associated only with dominant inheritance, never with recessive inheritance. The following pedigree illustrates incomplete penetrance in a known autosomal dominant disease.

external image pedigree2.gif

In the above pedigree, there is ample evidence for autosomal dominant inheritance:

  • The disease is passed from the father (II-3) to the son (III-5), this never happens with X-linked traits.

  • The disease occurs in three consecutive generations, this never happens with recessive traits.

  • Males and females are affected, with roughly the same probability.

  • However, II-1 does not express the disease. He must have inherited the mutant allele because he passed it on to two children, III-1 and III-3. II-1 is a classical example of incomplete penetrance, he has the allele for the disease but he does not express it.