Single gene mutation
Type of genetic disease
1. Single gene (Mendelian)
Autosomal dominant
Autosomal recessive
X linked recessive
Total
Chromosomal changes
Disease with genetic base
Congenital malformations
Total
Prevalence per 1000
2-10
2
1-2
5-12
6-7
7-10
20
38-51
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.
 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 the pedigree diagram.
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.
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.
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
Clues that suggest a Mendelian disease
1. Positive family history.
2. Characteristic syndrome.
3. Unusual syndrome
4. Progressive neurologic deterioration.
5. Multiple organ system abnormalities.
6. Intermittent neurologic symptoms.
7. Lack of environmental or other primary cause of symptoms and signs.
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:
1. There is a new mutation.
2. There is reduced penetrance of the phenotype.
 The age of onset varies.
 The severity of conditions is variable and diffeculte to predict.
 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.
 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
Homozygosity for a dominant disorder
Uncommon unless two people with the same disorder marry.
The risk is
25% homozygous affected (lethal).
50% heterozygous affected.
j25% homozygous normal.
Homozygosity for a dominant disorder
Homozygous affected
Heterozygous affected
Dominant disorder with lack of penetrance
1. 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%.
2. 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
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.
• 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.
• 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.
 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
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.
Consanguinity
parents are more likely to carry the increases the risk of a recessive disorder (both same
defective gene).
Examples of autosomal recessive disorder
• Thalassaemia.
• Cystic fibrosis.
• Galactosaemia.
• Sickle cell disease.
• Hurler’s syndrome.
• Haemochromatosis.
•
Congenital adrenal hyperplasia.
Autosomal recessive disorder
Aa
Aa
A
a
AA
1
25 %
Aa
:
2
25 %
A
a
Aa
aa
:
1
25 %
X-linked inheritance
Affected male and a normal female
The trait is never passed to son, all female affected

X

Healthy

Healthy
X
X

Healthy

Healthy

Healthy

Healthy
XLi
nk
ed
R
ec
es
si
ve
In
he
rit
an
ce
Consanguinity and autosomal recessive inheritance
Normal male and affected female
1/2 the sons affected and 1/2 the daughters affected


Affected

Healthy

Healthy

Affected