Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian)...
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Transcript of Prevalence of genetic disease Type of genetic disease Prevalence per 1000 1. Single gene (Mendelian)...
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
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.
Distribution of Mendelian disorders
0
10
20
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40
50
60
70
80
90
100
Autosomal dominant
Autosomal recessive
X-linked
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
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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
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.
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
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.
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 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.
Examples of autosomal recessive disorder
• Thalassaemia.
• Cystic fibrosis.
• Galactosaemia.
• Sickle cell disease.
• Hurler’s syndrome.
• Haemochromatosis.
• Congenital adrenal hyperplasia.
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-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
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