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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. For rare disorders e.g. Wilson's disease cousin marriages would be more frequent.

· The following pedigrees are commonly found in autosomal recessive inheritance (a) with unrelated parents; (b) with consanguineous parents.

·

It is to be noted that affected individuals arise only if both parents are heterozygous for the same gene. This is quite obvious for most conditions e.g. if one parent is a carrier (heterozygous) for B1 gangliosidosis and the other parent is a carrier for phenylketonuria, there is no increased risk to the offspring. However, several different genes may cause autosomal recessive congenital deafness. If the parents were both carriers for the same gene, the risk for the offspring would be 1 in 4. However, if the parents are carriers for different recessive genes causing congenital deafness, there is no increased risk for their offspring.

· In many cases there is only one affected child and the family history is negative. The pedigree in such cases would not be informative. The clinician usually identifies an autosomal recessive disorder from the clinical features and not from the pedigree. In small families in which the parents are both carriers for the same gene, there may be no affected individuals. Conversely, the greater the number of sibs, the more likely it is that at least one individual will be affected. In recent times most families have few children so that the typical pedigree with two or more affected sibs is becoming less common.

SEX-LINKED DISORDERS

X-LINKAGE

Sex-linked genes are those that are situated on the sex chromosomes. Over 140 genes are X-linked. Very few of these genes are related to sexual development. The vast majority are somatic genes affecting various body functions such as blood clotting, colour vision, body stature, and various metabolic processes. They are equally important in males and females. There are very few Y-linked genes and these are almost all related to male sexual development. Obviously, Y-linked genes are found only in males. Because so few genes are located on the Y chromosome, the term "sex-linked" is often taken to mean "X-linked" and the two terms are used interchangeably. Y-linked genes are important only in discussing sexual development.

We will take haemophilia as an example of an X-linked recessive disorder. The abnormality is due to a defective gene that produces factor VIII, one of the factors necessary for blood coagulation.

We will call the normal gene for factor VIII, X’, and its mutant allele responsible for haemophilia X^h.

· Females have two X chromosomes and so three possible genotypes:

X'X' X'X^h X^hX^h.

· Males have only one X chromosome and so only two possible genotypes:

· X' - X^h -.

The genotypes for X-linked genes in males are termed hemizygous (Greek, hemi- = half). The terms homozygous and heterozygous apply only for females. In X-linked conditions heterozygous females (X'X^h) are carriers and phenotypically normal; males may be either normal (X' -) or affected (X^h -) hemizygotes. The possible offspring resulting from affected individuals and carriers are shown in the Punnett Squares below.

CRITERIA OF X-LINKED RECESSIVE INHERITANCE

· With few exceptions, the trait occurs only in males

· The trait is transmitted from carrier females to affected males.

· Male to male transmission excludes X-linked inheritance.

The male offspring of an affected male individual are all normal; the female offspring are all carriers.

· An affected female is extremely rare and can only be the daughter of an affected male and a carrier female.

The pedigree below is typical of X-linked recessive inheritance. The allele (X’) is transmitted from female to male and male to female.

The trait is expressed only in males and is transmitted by females.

It is often described as a cris-cross pattern of inheritance because the disease appears in uncles and nephews. The trait is not transmitted in direct lineage, but appears to "skip a generation".

Note that the pedigree may be similar to that of autosomal dominant inheritance with reduced penetrance as is shown in the figure below. This also appears to skip a generation. Individual II3 in this pedigree must be heterozygous but does not show obvious symptoms of the disease. The distinguishing feature of theis pedigree is that it shows male to male transmission (I1 and II5), which is never seen in X-linked inheritance.

SOME X-LINKED TRAITS IN HUMANS

1. Haemophilia is characterised by inability to form blood clots because of deficiency of factor VIII, a clotting factor in the blood. The frequency of haemophiliacs is about 1 in 10,000 males. Affected individuals suffer from severe bleeding following a relatively small injury e.g. a cut or a bruise. Bleeding into the joints may occur leading to arthritis and joint stiffness. These complications may be avoided if affected individuals learn how to self-administer factor VIII in case of injury and to keep a stock of it at home.

2. Christmas disease is similar to Haemophilia but is due to deficiency of factor IX. The gene for factor IX is also X-linked but is at a different locus from that of factor VIII.

3. Duchenne Muscular Dystrophy affects young boys. It is characterised by muscular degeneration and weakness beginning at the age of 3 to 5 years and progressing rapidly so that affected individuals are wheel-chair bound by the time they are in their teens and die in their early twenties because of severe involvement of their respiratory muscles. There is deficiency of the protein dystrophin in skeletal muscle, caused by a mutation of the dystrophin gene.

4. Becker muscular dystrophy also affects males but muscular weakness begins in adolescence, the condition progresses slowly and is not lethal. It is also caused by a mutation of the dystrophin gene, the same gene that produces Duchenne muscular dystrophy, but in this case the protein dystrophin is only slightly abnormal.

5. Red-green colour blindness is the inability to distinguish red from green. There are two adjacent genes on the X-chromosome, both related to colour vision. One of theses genes produces a retinal pigment for red colour perception and the other produces a pigment for green colour perception. A mutation affecting one or the other gene causes partial red-green colour blindness while mutations affecting both genes causes total red-green colour blindness.

6. Glucose-6-phosphate dehydrogenase (G-6PD) deficiency is caused by deficiency of the enzyme G-6PD that plays a key role in glucose metabolism. When persons with this deficiency ingest certain drugs or foodstuffs, particularly the broad bean vicia fava, there is haemolysis that causes anaemia. The symptoms of the condition can be prevented if care is taken to avoid ingestion of the offending foods.

X-LINKED DOMINANT DISEASES

An example is Vitamin D-resistant rickets. This results from a defect in vitamin D metabolism. Unlike the common type of rickets, it does not respond to therapeutic doses of vitamin D. Being X-linked dominant, it affects heterozygous females (X'X^h) as well as hemizygous males (X^h -). The Punnett squares for X-linked recessive traits shown above still apply with the difference that female heterozygotes are affected. The pattern of transmission is very similar to that of autosomal dominant conditions but male-to-male transmission never occurs. An affected mother will have half her sons and daughters affected. An affected male will have all his daughters affected but all his sons will be normal.

THE LYON HYPOTHESIS: X- INACTIVATION

X-linked genes are all paired in females but are present as single copies in males. This implies that only a single copy of these genes is necessary for normal function. One would expect that the proteins regulated by the X-linked genes would be present in half the amounts in males as compared to females. However, this is not so. The amount of protein produced is approximately equal in males and females. The Lyon hypothesis, proposed by the geneticist Mary Lyon in 1961, states that only one X chromosome is active in any cell and that any X chromosomes in excess of one are inactivated.

The phenomenon of X inactivation can be observed in the cells of females: the inactivated X chromosome forms a tightly coiled clump of chromatin which is visible in the nuclei of cells as a mass adjacent to the nuclear envelope and known as a Barr body. As a result there is only one functional X chromosome in both males and females. This phenomenon is known as dosage compensation.

The Lyon hypothesis can be verified in individuals with numerical X chromosome abnormalities. Males, who have 47, XXY chromosomes (Klinefelter Syndrome) have one Barr body. Males with 48,XXXY chromosomes and females with 47,XXX chromosomes (trisomy X) both have two Barr bodies. In contrast females with Turner Syndrome (45, X chromosomes) and normal males (46, XY) have no Barr bodies. It is now clear that monosomies, trisomies and tetrasomies of the X chromosomes, are compatible with life because of the phenomenon of X inactivation. However, it is also clear that X-inactivation is only partial, since the persons affected with the above mentioned sex-chromosome abnormalities have defects affecting both somatic and sexual development.

X-INACTIVATION IS RANDOM.

Which of the two X chromosomes is inactivated in females is purely random. Let us consider a particular locus on the X chromosome, such as that of haemophilia (factor VIII) in a heterozygote (carrier female). In about half the cells the X chromosome bearing the normal allele would be inactivated and in the other half the X chromosome bearing the mutant allele for haemophilia would be inactivated. Thus only half the cells would produce factor VIII and only half the amount of factor VIII would be present in the circulation. However, this is sufficient for normal blood clotting.

Random X inactivation occurs during foetal development. In some cells, the maternally- derived X chromosome is inactivated, while in others the paternally derived X chromosome is inactivated. The mass of cells, which arise by mitosis from one particular cell, is called a clone. After X inactivation during foetal life, all the cells of one clone would have the same X chromosome inactivated.

Random X inactivation can be observed dramatically in female "tortoise shell" cats, which have patches of black fur and patches of rust coloured fur. The genes for black and rust hair pigment are alleles situated on the X chromosome; we will these call X^b and X^r respectively. In heterozygous females (X^b X^r ) some skin cells will have the X^b allele inactivated and produce patches of rust coloured fur, while others will have the X^r gene inactivated and produce patches of black fur.

A similar example of random X inactivation in humans is seen in X-linked ectodermal dysplasia. Males having the mutant X-linked gene (X^m -) have no sweat glands (with consequent heat intolerance), have scanty body hair, early baldness and abnormal teeth. Females heterozygous for the X-linked mutant allele (X' X^m ) have patches of skin in which sweat glands are absent.

SEX-INFLUENCED INHERITANCE

Sex-influenced conditions are to be distinguished from X-linked recessive conditions. The genes responsible for sex influenced inheritance are autosomal but their expression is influenced by sex. For example an autosomal dominant gene causes male pattern baldness. The condition is expressed only in males. Its expression is dependent on the presence of high levels of testosterone. Females may also inherit the gene and transmit it to their offspring but do they do not express the trait because they have a low testosterone level. The trait is expressed only in males but, unlike X-linked inheritance, male to male transmission occurs as well as transmission through carrier females.

PROBLEMS

1. A man with red-green colour blindness is married to a girl with normal colour vision. What is the probability that his children will be colour blind?

2. A boy has Duchenne muscular dystrophy. His maternal uncle had died of muscular dystrophy at the age of 21 years. What is the probability that this child's sibs will be affected?

3. The adjacent pedigree is of a family with haemophilia. If the gene for haemophilia is represented by X^h and the normal allele by X', write the genotypes of each individual in the pedigree. If the genotype cannot be determined with certainty write the possible alternatives.

4. Explain, giving reasons, whether the following pedigrees are compatible with autosomal dominant, autosomal recessive or X-linked dominant and X-linked recessive inheritance. (Note that a pedigree may be compatible with more than one type of inheritance.)

a.

b.

c.

5. Examine the pedigree from a family with a genetic disease and answer the questions below:

a. Does this pedigree indicate autosomal dominant, recessive or sex-linked type of inheritance? Give reasons for your choice.

b. Assuming that B and b are the normal and mutant alleles respectively, what would be the genotypes of the individuals: II.1, II.2 and III.3 ?

c. Individual II.3 requested genetic counselling. What is the probability that her child would be affected. Explain why.

6. A young lady requested pre-marital genetic counselling because her sister had died in infancy of gangliosidosis, an autosomal recessive disease. What is the risk that this young lady has similarly affected offspring? What advice should be given?

7. A young man requested pre-marital genetic counselling because his brother is an achondroplastic dwarf. This condition is inherited as an autosomal dominant disorder. What is the risk that his offspring will be similarly affected? What advice should be given?

8. A young couple had their first child affected with cystic fibrosis. What is the risk that their future children will be similarly affected?

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