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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
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 definition
Alleles: 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 know
Hemizygous: 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
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.
Trait
Definition
Gene-determined characteristics.
Types
1. 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
100
90
80
70
60
50
40
30
20
10
0
Autosomal dominant
Autosomal recessive
X-linked
Frequency of Mendelian diseases by organ system
Organ system
Respiratory
Endocrine
Nails
Immune
Hair
Teeth
Circulatory
Ear
Gastrointestinal
Limbs
Blood
Gentourinary
Metabolic
Craniofacial
Skin
Eye
Musculoskeletal
Nervous system
Integument (includes skin, hair and nails)
Percent of
phenotypes
with system
affected
1
4
5
5
6
8
9
9
9
10
11
13
15
16
21
28
30
34
35
Recessive
Allele
6
5
4
3
2
1
I have to
be in
charge
now!
Damaged
Allele
6
5
4
3
2
1
4
4
3
3
2
2
1
1
1
1
2
2
3
3
1
1
2
2
3
3
4
4
5
5
6
6
Pedigree
Marriage
Unaffected
Offspring illegitimate
Affected
Marriage consanguineous
Propositus
Twins dizygous
Heterozygous gene carier
Autosomal recessive
Heterozygous gene carier
X-Link recessive
Twins monozygous
Subject without offspring
Deceased
Sex unknown
Abortion or stilbirth
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
Dominant
6
5
2
Quit ! I will
speak for
both of us
Normal
6
5
4
4
3
3
2
2
1
1
1
4
4
3
3
2
2
1
1
1
1
1
2
2
3
3
1
1
2
2
3
3
4
4
5
5
6
6
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.
Transmision
 A 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.
Autosomal dominant disorder
Parents
Gametes A
Offspring Aa
aa
Aa
a
Aa
1:1
a
a
aa
aa
Altered 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 Recessive
Trait (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.
Inheritance
Recognized 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 disorders
Examples of autosomal recessive disorder
• Thalassaemia.
• Cystic fibrosis.
• Galactosaemia.
• Sickle cell disease.
• Hurler’s syndrome.
• Haemochromatosis.
• Congenital adrenal hyperplasia.
Consanguinity and autosomal
recessive 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
Menelian Inheritance
X-link dominant disorder
• Incontinentia pigmenti.
• Rickets resistant to vitamin D.
X-link recessive disorder
• Glucose-6-phosphate dehydrogenase.
• Duchenne muscular dystrophy.
• Haemophilia A, B.
• Ocular albinism.
• Color blindness.
Affected male and a normal female
The trait is never passed to son, all female affected


X

Healthy
X
X


Healthy


Healthy
Normal male and affected female
1/2 the sons affected and 1/2 the daughters affected


Affected

Healthy

Healthy

Affected
Hypophosphatemia
Autosomal recessive disorder
Aa
Aa
A
a
AA
1
25%
Aa
:
2
25%
A
a
Aa
aa
:
1
25%
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 Xinactivation.
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 father
Never any Male-to-Male transmission!
Normal Female
Parents
Gametes
Offspring
XX
X
X
Affected Male
XhY
Xh
Y
hX
XhX
X
XY
XY
2 carrier daughters : 2 normal sons:
X linked recessive, normal
father, carrier mother
1 carrier daughter
1 normal daughter
1 affected son
1 normal son
A typical X-linked recessive pedigree