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Prevalence of Prevalence of genetic disease genetic disease Type of genetic disease Prevalence per 1000 1. 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 20
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Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Dec 25, 2015

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Page 1: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 2: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

History

Gregor Mendel(1822-1884)

Page 3: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 4: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 5: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 6: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 7: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 8: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 9: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Modes of Inheritance

Autosomal recessive.

Autosomal dominant.

X-linked dominant.

X-linked recessive.

Y-linked.

Mitochondrial.

Page 10: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Most genetic diseases manifest during childhood

Page 11: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Distribution of Mendelian disorders

0

10

20

30

40

50

60

70

80

90

100

Autosomal dominant

Autosomal recessive

X-linked

Page 12: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Frequency of Mendelian diseases by organ system

Page 13: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 14: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 15: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Pedigree symbols

Page 16: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 17: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 18: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Autosomal dominant

disorders

Page 19: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 20: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 21: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 22: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 23: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 24: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 25: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.
Page 26: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Aa

A a

aa

a a

Aa aa aaAa

Parents

Gametes

Offspring

1 : 1

Autosomal dominant disorderAutosomal dominant disorder

Page 27: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Altered Dominant GenesAltered Dominant Genes

Page 28: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 29: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Homozygosity for a dominant disorder

Homozygous affected

Heterozygous affected

Page 30: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 31: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 32: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.
Page 33: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Autosomal recessive disorder

Page 34: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 35: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 36: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 37: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 38: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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).

Page 39: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 40: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Autosomal recessive disordersAutosomal recessive disorders

Page 41: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Examples of autosomal recessive disorder

• Thalassaemia.

• Cystic fibrosis.

• Galactosaemia.

• Sickle cell disease.

• Hurler’s syndrome.

• Haemochromatosis.

• Congenital adrenal hyperplasia.

Page 42: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Consanguinity and autosomal Consanguinity and autosomal recessive inheritancerecessive inheritance

Page 43: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 44: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 45: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

X-linked inheritance

Page 46: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 47: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

X X X

Healthy Healthy Healthy

Page 48: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Affected Healthy Affected

Normal male and affected female

Healthy

Page 49: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

Hypophosphatemia

Page 50: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.
Page 51: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 52: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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?

Page 53: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 54: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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.

Page 55: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

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

Page 56: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

X linked recessive, normal father, carrier mother

1 carrier daughter1 normal daughter1 affected son1 normal son

Page 57: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.
Page 58: Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian) Autosomal dominant Autosomal recessive X linked recessive.

A typical X-linked recessive pedigree