Prevalence of genetic diseasePrevalence of genetic diseaseType of genetic disease Prevalence per 10001. Single gene (Mendelian)

Autosomal dominant

Autosomal recessive

X linked recessive

Total

2-10

2

1-2

5-12

Chromosomal changes 6-7

Disease with genetic base 7-10

Congenital malformations

Total

20

38-51

History

Gregor Mendel(1822-1884)

The burden of Mendelian (single gene) disorders

• Although individually rare, genetic diseases

collectively constitute a major health problem.

• About 5 - 8 % of admissions to a pediatric hospital and

about 1 % of admissions to an adult hospital are for

Mendelian disorders.

• 9 % of pediatric deaths are due to Mendelian disorders

• About 1- 2 % of the population has a Mendelian

disorder.

• Most Mendelian disorders are apparent by childhood.

• Life span is reduced in about 60 % of these disorders.

• Each person is estimated to have 1 - 5 lethal recessive

alleles.

Importance of recognizing Mendelian disorders

Establishment of definitive diagnosis.

Recognition of other relatives with disease

or at risk for disease.

More accurate prognosis can be given

Anticipation/prevention of complications,

both medical and emotional/psychological

More informed family planning.

Important definitionAlleles: Alternative forms of a gene that can be distinguished

by their alternate phenotypic effects or by molecular

differences; a single allele for each locus is inherited separately

from each parent.

Autosome: One of chromosomes 1 – 22.

Dominant allele: An allele whose phenotype is detectable

(even if only weakly) in a single dose or copy.

Recessive allele: An allele whose phenotype is apparent

only in the homozygous or hemizygous state.

Heterozygous: Having a normal allele on one chromosome

and a mutant allele on the other.

More terms to knowHemizygous: Having half the number of alleles (e.g.

males are hemizygous for all X chromosome genes)

Expressivity: The severity or intensity of the

phenotype of an allele.

Penetrance: The degree to which a gene expresses

any observable phenotype

Locus (pl. loci): The position on a chromosome of a

gene or other chromosome marker; also, the DNA at

that position.

Proband: The first affected individual who comes to

clinical genetic evaluation. Indicated by an arrow on

the pedigree diagram.

Definition In normal human we have:22 homologous pairs of chromosomes.

Autosomal genes are present in pairs, one

maternal and the other paternal.

Homozygous: Both gene pair are identical.

Heterozygous: Different.

Trait: Gene-determind characteristic.

TraitDefinition

Gene-determined characteristics.

Types1. Dominant trait Express in the heterozygote.

2. Recessive trait Express in the homozygote.

3. Codominant trait

The effect of both alleles is seen in heterozygot.

Modes of Inheritance

Autosomal recessive.

Autosomal dominant.

X-linked dominant.

X-linked recessive.

Y-linked.

Mitochondrial.

Most genetic diseases manifest during childhood

Distribution of Mendelian disorders

0

10

20

30

40

50

60

70

80

90

100

Autosomal dominant

Autosomal recessive

X-linked

Frequency of Mendelian diseases by organ system

6

5

4

3

2

1

4

3

2

1

1

2

3

1

2

3

4

5

6

Recessive Allele

6

5

4

3

2

1

4

3

2

1

1

2

3

1

2

3

4

5

6

I have to be in

charge now!

Damaged Allele

Pedigree

Unaffected

Affected

Propositus

Heterozygous gene carierAutosomal recessive

Heterozygous gene carierX-Link recessive

Deceased

Sex unknown

Subject without offspring

Abortion or stilbirth

Offspring illegitimate

Marriage consanguineous

Twins dizygous

Twins monozygous

Marriage

Pedigree symbols

Clues that suggest a Mendelian disease

• Positive family history.

• Characteristic syndrome.

• Unusual syndrome

Progressive neurologic deterioration.

Multiple organ system abnormalities.

Intermittent neurologic symptoms.

• Lack of environmental or other primary cause of symptoms and signs.

Taking a family history• Inquire about the health of each family member

through second degree relatives (grandparents, first

cousins).

• Pay special attention to any signs or symptoms related

to your patient’s condition in relatives.

• Inquire about causes of any deaths, including any

stillbirths or early deaths, institutionalizations.

• Obtain medical (and death) records of relatives as well

as of proband.

• Inquire about any possible consanguinity.

• Recognize that false paternity does occur.

Autosomal dominant

disorders

2

1

1

6

5

4

3

2

1

4

3

2

1

1

2

3

1

2

3

4

5

6

3

6

5

4

3

2

1

4

3

2

1

1

2

3

1

2

3

4

5

6

NormalDominant Quit ! I will Quit ! I will speak for speak for both of usboth of us

Autosomal dominant disorders

Autosomal dominant disorders

comprise the majority (about 68%) of

known human Mendelian conditions.

Clear evidence of transmission

from one generation to the next.

Genearl characteristics Generally there is a family histry of the same

disorder.The phenotype appears in every generation.

a. Each affected individual has an affected parent.

b. Exceptions to this rule occur if:

There is a new mutation.

There is reduced penetrance of the phenotype.The age of onset varies.The severity of conditions is variable and

diffeculte to predict.

Autosomal dominant

Phenotypically normal parents do not

transmit the trait, unless there is lack

of penetrance, or the apparently 'normal'

parent has unrecognized signs.

Affected people are heterozygous for

the abnormal allele.

Autosomal dominant traits Every affected individual should have at

least 1 affected parent.

Affects males and females equally.

Homozygous dominant condition is

often

fatal.

Difficult to determine with small families.

TransmisionA child of an affected parent has a 50% chance of

inheriting the trait.

Males and females are equally at risk.

Affected individuals may have unaffected

children.

Males can transmit to males or femaless and vice

versa.

Unaffected persons do not transmit the condition.

Male to male transmission occurs.

Aa

A a

aa

a a

Aa aa aaAa

Parents

Gametes

Offspring

1 : 1

Autosomal dominant disorderAutosomal dominant disorder

Altered Dominant GenesAltered Dominant Genes

Homozygosity for a dominant disorder

Uncommon unless two people with the

same disorder marry.

The risk is

25% homozygous affected (lethal).

50% heterozygous affected.

25% homozygous normal.

Homozygosity for a dominant disorder

Homozygous affected

Heterozygous affected

Dominant disorder with lack of penetrance

Seen in person who inherits the gene but he does not devolop the disorder.

The risk of such people to transmit the

disorder to their children is about 10%.Non-genetic factor favor the expresion of

dominant genes.

Example: Drug in porphyria.

Diet in hypercholesterlaemia.

Example of autosomal dominant disorder

• Achondroplasia.

• Mytonic dystrophy.

• Tuberous sclerosis.

• Noonan’s syndrome.

• Huntington’s disease.

• Epidermolysis bullosa.

• Adult polycystic kidney.

• Familial hypercholesterolaemia.

• Familial adenomatous polyposis.

Autosomal recessive disorder

Autosomal RecessiveTrait (e.g. disease) due to absence of normal

gene, since autosomal (and therefore two

copies of each chromosome) requires two

abnormal gene copies (i.e. alleles). Therefore,

abnormal gene must come from both parents.

Autosomal recessive traits

• Males and females equally affected.

• 1/4 of offspring will be affected.

• Trait typically found in siblings, not parents.

• Parents of affected children may be related.

• Trait may appear as isolated event in small

families.

InheritanceRecognized by:

a. 1/4 th of offspring affected

b. males = females among affected.

c. In general, parents unaffected.

d. For rare disorders, increased consanguinity.

Autosomal recessive inheritance

• The risk to each sib of an affected individual of showing the phenotype

is 25 %.

• Consanguinity significantly increases the risk of manifesting a recessive phenotype.

• Males and females are equally likely to be affected.

• Ethnicity and geographic isolation may affect the frequency of recessive conditions in a population.

Autosomal recessive disorder• Occur in the offspring of a carrier parents.• The risk for the offspring is 25%.• There is no family history in general.• Commonly severe.• Prenatal diagnosis for recessive disorder is indicated after the 1st affected child.

Consanguinity parents are more likely to carry the increases the risk of a recessive disorder (both same defective gene).

How did they get this frequent?

Two mechanisms:

1) Selection, e.g. heterozygote advantage

against malaria in sickle cell disease.

2) Genetic drift, founder population of

relatively small sample size.

Autosomal recessive disordersAutosomal recessive disorders

Examples of autosomal recessive disorder

• Thalassaemia.

• Cystic fibrosis.

• Galactosaemia.

• Sickle cell disease.

• Hurler’s syndrome.

• Haemochromatosis.

• Congenital adrenal hyperplasia.

Consanguinity and autosomal Consanguinity and autosomal recessive inheritancerecessive inheritance

Disease Ethnic Group Frequency

• Sickle cell disease African-American 1/600

• Beta-thalassemia Italians, Greeks 1/3600

• Alpha-thalassemia Southeast Asians 1/2500

• Familial mediterranean fever Armenians/N.

African Jews 1/200

Sickle cell• Sickle trait (the presence of any HbS) is

dominant, but is generally asymptomatic unless extremely hypoxic (e.g. unpressurized at high altitude)

• Sickle cell anemia is recessive• Clinical syndrome:

– Painful abdominal and bone crises brought out especially by hypoxia, but often unpredictable

– Complications include infarcts of internal organs and joints

– May autosplenectomize, leading to predisposition to infections

X-linked inheritance

X-link dominant disorder• Incontinentia pigmenti.• Rickets resistant to vitamin D.

X-link recessive disorderX-link recessive disorder• Glucose-6-phosphate dehydrogenase.Glucose-6-phosphate dehydrogenase.• Duchenne muscular dystrophy.Duchenne muscular dystrophy.• Haemophilia A, B.Haemophilia A, B.• Ocular albinism.Ocular albinism.• Color blindness.Color blindness.

Menelian Inheritance

Affected male and a normal femaleThe trait is never passed to son, all female affected

X X X

Healthy Healthy Healthy

1/2 the sons affected and 1/2 the daughters affected

Affected Healthy Affected

Normal male and affected female

Healthy

Hypophosphatemia

Aa

A a

Aa

A a

AA Aa aaAa

1 : 2 : 11 : 2 : 1

25%25% 25%25% 25%25%

Autosomal recessive disorderAutosomal recessive disorder

Trait• Males are usually more severely

affected than females.

• The trait may be lethal in males.

• In the general population, females are

more likely to be affected than males

Why?

X-Linked Recessive Inheritance

• Trait is more common in males than females.

• An affected man passes the gene to all of his daughters.

• A son of a carrier mother has a 50 % chance of inheriting

the trait.

• Male-to-male transmission never occurs.

• Carrier females are usually asymptomatic, but some may

express the condition with variable severity because of X-

inactivation.

X-link recessive• As with any X-linked trait, the disease is never

passed from father to son.• Males are much more likely to be affected than

females. If affected males cannot reproduce, only males will be affected.

• All affected males in a family are related through their mothers.

• Trait or disease is typically passed from an affected grandfather, through his carrier daughters, to half of his grandsons.

X-linked recessive, affected fatherNever any Male-to-Male transmission!

2 carrier daughters : 2 normal sons:

Affected MaleNormal Female

XX

X X

XhY

Y

XhX XhX XYXY

Parents

Gametes

Offspring

Xh

X linked recessive, normal father, carrier mother

1 carrier daughter1 normal daughter1 affected son1 normal son

A typical X-linked recessive pedigree