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MONOGENIC INHERITANCE:

OBJECTIVES:

· By the end of this session the student should be able to:

· State the differences between autosomal and X-linked, dominant and recessive inheritance

· Give examples of diseases showing different types of monogenic inheritance

· Explain the meaning of new mutations, penetrance and expressivity

· Explain the importance of consanguinity in autosomal recessive disorders

· Calculate the expected frequencies of affected individuals and carriers in monogenic diseases

· Define the terms heterozygous, homozygous, and hemizygous

· Explain why females are rarely affected by X-linked recessive diseases

MONOGENIC INHERITANCE

This chapter concerns the inheritance of characteristics that are determined by a single gene pair. These are characteristics showing discontinuous variation i.e. those represented by two or more contrasting characteristics. There are few easily visible, normal external characteristics that show monogenic inheritance. Examples are eye colour, large or small ear lobes, sticky or dry earwax, ability or inability to curl the tongue (tongue rolling), ability or inability to taste the substance PTC, ability or inability to hyperextend the thumb (hitch hiker's thumb). However, there are numerous examples of diseases that follow a monogenic pattern of inheritance.

In humans, most visible characteristics such as stature, blood pressure and intelligence show continuous variation. Each of these characteristics is represented by a range of values. Such characteristics are determined by several genes, which also interact with the environment, and therefore show polygenic inheritance. For example stature is determined by a number of inherited genes, but a high nutritional level during childhood also contributes to increase stature.

Inherited genetic diseases are examples of discontinuous variation. The disease is either present or is not, and there is no intermediate range. They show monogenic inheritance.

· Genes always go in pairs.

Alleles are the possible alternative forms of the same gene. The alleles in a gene pair may be identical or different.

The genotype is the particular combination of genes in an individual.

The phenotype is the sum total of the physical characteristics resulting from the expression of the gene pair (genotype) in an individual.

In this chapter it will be assumed that there are:

two possible alleles: A a

three possible genotypes: A A A a a a

two possible phenotypes: dominant recessive

For each pair of contrasting characteristics (phenotypes), one characteristic is dominant and the other is recessive. The dominant characteristic is the one that manifests itself in the heterozygote (Aa) as well as in the dominant homozygote (AA), whereas the recessive characteristic manifests itself only in the recessive homozygote (aa).

AUTOSOMAL AND X-LINKED INHERITANCE

· Autosomal inheritance applies to genetic disorders that are determined by a gene pair situated on the autosomes, i.e. the chromosomes other than the sex chromosomes X or Y, whereas X-linked disorders those that are determined by genes situated on the X chromosome. The main difference stems from the fact that there is only one X chromosome in males so that X-linked genes are unpaired in males, and paired in females. This gives rise to important differences in the transmission of X-linked diseases.

CRITERIA FOR AUTOSOMAL DOMINANT INHERITANCE

An autosomal dominant trait:

* is one that manifests itself in the heterozygote

* is equally represented in males and females

* shows vertical inheritance through generations i.e. transmission from parent to offspring

* affected parents have 50 chance that their offspring will be similarly affected.

The outcome in the offspring can be worked out using Punnett squares (a) if one parent is affected; (b) if both parents are affected, as shown in the figures below.

(a)
	Affected Parent
Normal Parent	A	a
a	A a	a a
a	A a	a a
	50% Affected	50% Normal

(b)
	Affected Parent
Affected Parent	A	a
A	A A	A a
a	A a	a a
	75% Affected	25% Normal

A dominant homozygote (AA) can only result from two affected parents. As these diseases are rare, two parents affected by the same autosomal dominant disorder would be extremely rare, and so the dominant homozygote is practically never seen. Now, you can work out the outcome for the offspring of an individual who is a dominant homozygote (AA) and a heterozygote (Aa) partner.

Families with an autosomal dominant disorder usually show a characteristic pedigree with vertical transmission from parents to offspring and affecting both sexes. The arrow indicates the propositus, the individual who presented for investigation.

EXAMPLES OF AUTOSOMAL DOMINANT DISORDERS

Achondroplasia: a type of dwarfism characterised by short limbs, a normal-sized trunk and various skeletal abnormalities.

Adult polycystic kidney disease: multiple cysts in the kidneys and liver causing symptoms and complications in adult life and leading to progressive renal failure;

Brachydactyly: meaning short fingers or toes. Usually, the middle phalanx is short. There are several varieties. In most cases it causes no inconvenience to affected individuals.

Congenital Spherocytosis: the red blood cells are in the form of spheres rather than flat biconcave discs; they cause anaemia.

Familial Adenomatous Polyposis (FAP): numerous polyps in the large intestine becoming cancerous in most cases.

Familial Hyperlipidaemia: elevated blood levels of low-density lipoproteins predisposing to coronary heart disease at a young age. This is the commonest autosomal dominant disorder.

Huntington's disease: a late-onset neurological disorder, appearing usually around the age of 35 years and characterized by abnormal, involuntary writhing movements (chorea) and behaviour and personality disorders. It is a severely incapacitating and progressive disorder resulting in early death.

Marfan's syndrome: a disorder of connective tissue. It causes abnormalities of the skeleton including tall stature, wide arm span, spidery fingers and deformities of the sternum; cardiovascular abnormalities such as aortic aneurysm or heart valve incompetence; and subluxation of the lens.

Neurofibromatosis: characterized by numerous cafe-au-lait pigmented patches and multiple benign tumours of the nerve sheaths (neurofibromas) causing irregular swellings in the skin

Postaxial Polydactyly: characterised by an extra digit on the side of the little finger or little toe, which may vary from a small tag to a well-developed digit. The extra digit is usually removed in early infancy and forgotten.

Tuberous sclerosis (adenoma sebaceum): characterised by an adenomatous rash on the cheeks, calcifications in the brain and fits.

SITUATIONS THAT MAY MODIFY THE PATTERN OF AUTOSOMAL DOMINANT INHERITANCE

Some autosomal dominant disorders do not always appear to follow the general rules stated above. Some cases do not have the characteristic pedigree and have a negative family history. This may be due to one of the following phenomena:

1. Conditions that manifest themselves late in life.

The typical example is Huntington's disease. Although the gene for Huntington's disease is present from the time of conception, affected individuals are normal until symptoms appear, usually around the age of 45 years. Many individuals who carry the abnormal gene marry and have children before the disease appears. The age at onset of the disease is very variable ranging from 20 to 70 years. Some individuals who have the abnormal gene might die from unrelated causes before the disease appears. Thus the pedigree may show an unaffected person who has affected offspring.

2. New Mutations

Autosomal dominant conditions that have a negative family history are usually the results of new mutations. Individuals with a severe disorder such as achondroplasia often have reduced chances of getting married and having children, because of medical or social reasons. Achondroplastic dwarfs have 50% of their children similarly affected. Most cases of achondroplasia, however, have normal parents. These cases are the result of new mutations. For a normal couple who had a child with achondroplasia arising as a new mutation, there would be no increased recurrence risk for their other children. However, the affected child would have a 50% chance of having affected offspring.

· In general the more severe the disease, the greater is the proportion of cases arising as new mutations because the chances of affected individuals reproducing would be very small. The following are a few examples.

3. Variable Expressivity

There is often a considerable variation in the severity of the disorder or in the type of abnormalities present although the genetic defect is the same. This is referred to as variable expressivity. Most genetic diseases show some degree of variable expressivity. For example, in postaxial polydactyly the extra digit may vary from a small skin tag to a fully formed digit. In Marfan's syndrome affected individuals often do not have all the characteristics - one individual may present with tall stature and subluxated lens, another with an aortic aneurysm.

Sometimes the variability may be so great that there may be little resemblance in phenotypic manifestations of an affected individual and his affected offspring. For example, in one type of limb reduction deformity the disorder may be expressed to variable degrees from a missing finger to a missing leg.

4. Penetrance

In some cases individuals who carry an abnormal gene do not appear to manifest any symptoms of the disease, although their offspring may be affected and it would appear in the pedigree that the disease has "skipped a generation". The reason for this could be reduced penetrance. Penetrance is a measure of how frequently a gene is expressed. It is the proportion of heterozygotes who manifest the disorder. Some autosomal dominant conditions e.g. achondroplasia have 100% penetrance i.e. when the gene is present the disease always express itself. In other conditions there may be reduced penetrance. Retinoblastoma is an autosomal dominant condition that has 85% penetrance i.e. only 85% of persons carrying the abnormal gene show symptoms of the condition; the remaining 15% never develop retinoblastoma but can still transmit the gene to their offspring. Penetrance is important in the assessment of recurrence risks.

CRITERIA FOR AUTOSOMAL RECESSIVE CONDITIONS

• The condition manifests itself only in homozygotes;
• The parents of an affected individual are both heterozygous (carriers) but are phenotypically normal;
• The condition is often present among sibs but is not usually transmitted through generations;
• The offspring of heterozygous parents have a 1 in 4 chance of being affected; the ratio of affected to normal offspring is 1 : 3.

· The following are some examples of autosomal recessive diseases:

Albinism: There is lack of pigment in the skin, hair and eyes due to a deficiency in one of the enzymes (e.g. tyrosinase) that is necessary for the formation of melanin pigment from tyrosine. Lack of pigment may cause visual problems and sensitivity of the skin to sunlight.

Beta Thalassaemia: The adult type of haemoglobin (Hb A) is not produced or is produced in very small amounts due to a defect in the production of beta-globin. This causes severe anaemia beginning in early childhood and requiring frequent blood transfusions. The bone marrow increases greatly in amount, trying to compensate for the anaemia, causing a thickening of the bones of the skull and face.

Congenital Hypothyroidism: This is due to lack of secretion of the hormone thyroxine. Severe mental retardation results unless replacement therapy with thyroxine is started in early infancy.

Cystic Fibrosis: A disorder in the secretions of glands affecting mainly the respiratory system, pancreas and sweat glands; death in infancy may result from recurrent severe pulmonary infections.

Galactosaemia: This is due to lack of an enzyme required to metabolise galactose. High levels of galactose are present causing mental retardation, cataracts and cirrhosis of the liver. These consequences can be prevented if the disorder is recognised and treated in early infancy using special milk substitutes that do not contain galactose and lactose.

Gangliosidosis: Deficiency of the enzyme beta galactosidase causes accumulation of ganglioside in the tissues including the brain, bone marrow, liver and spleen; involvement of the brain causes fits, severe mental deterioration. Death usually occurs in infancy.

Phenylketonuria: A defect in phenylalanine metabolism causing mental retardation unless a special diet is started early enough in infancy.

Sickle cell anaemia: A disorder of the haemoglobin molecule causing the red blood cells to become sickle shaped and rupture under conditions of low oxygen tension. This results in severe haemolytic anaemia.

The following Punnett Squares show the possible outcomes in the offspring of affected individuals and carriers for autosomal recessive disorders.

Parents	Normal Homozygote
Heterozygote	A	A	Offspring- all normal
A	AA	AA	^1/2 Homozygous - Normal
a	Aa	Aa	^1/2 Heterozygous - Carriers

a.

b.

c.

d.

The pedigree in autosomal recessive disorders typically shows two or more affected sibs in one family but other relatives are normal. This is sometiomes called “horizontal” inheritance. In some cases the parents are consanguineous. First cousins have 1 in 8 of their genes in common. Thus, if one individual were a carrier (heterozygous) for an autosomal recessive disorder, the chances that his or her first cousin is similarly affected would be 1 in 8. The risk for second cousins is 1 in 32, and is less for more distant relationships. However, in many cases of autosomal recessive disorder, the parents are not related. This is especially so in common disorders e.g. thalassaemia and cystic fibrosis.