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.
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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
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).