Transcript Mendelian Genetic Disease

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
Experimental genetics
Modern genetics began with Gregor Mendel’s •
quantitative experiments with pea plants
Stamen
Carpel
Figure 9.2A, B
• Mendel crossed pea
plants that differed in
certain characteristics
and traced the traits from
generation to generation
White
1
Removed
stamens
from purple
flower
Stamens
Carpel
PARENTS
(P)
2 Transferred
Purple
pollen from
stamens of white
flower to carpel
of purple flower
3 Pollinated carpel
matured into pod
• This illustration
shows his technique
for cross-fertilization
4
OFFSPRING
(F1)
Planted
seeds
from pod
FLOWER
COLOR
• Mendel studied seven pea
characteristics
• He hypothesized that
there are alternative
forms of genes
(although he did not
use that term), the units
that determine heredity
Purple
White
Axial
Terminal
SEED
COLOR
Yellow
Green
SEED
SHAPE
Round
Wrinkled
POD
SHAPE
Inflated
Constricted
POD
COLOR
Green
Yellow
STEM
LENGTH
Tall
Dwarf
FLOWER
POSITION
A sperm or egg carries •
only one allele of each
pair
GENETIC MAKEUP (ALLELES)
P PLANTS
Gametes
PP
pp
All P
All p
– The pairs of alleles
F PLANTS
separate when
(hybrids)
gametes form
Gametes
/ P
– This process
describes Mendel’s
law of segregation
Eggs
F PLANTS
p
– Alleles can be
ratio
dominant or recessive Phenotypic
3 purple : 1 white
1
1
All Pp
1/
2
P
Sperm
PP
p
Pp
Pp
pp
Figure 9.3B
p
P
2
Genotypic ratio
1 PP : 2 Pp : 1 pp
2
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.
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
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.
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.
2.4 Homologous chromosomes bear the
two alleles for each characteristic
Alternative forms of a gene (alleles) reside at the •
same locus on homologous chromosomes
GENE LOCI
P
P
a
a
B
DOMINANT
allele
b
RECESSIVE
allele
GENOTYPE:
PP
aa
HOMOZYGOUS
for the
dominant allele
HOMOZYGOUS
for the
recessive allele
Bb
HETEROZYGOUS
Figure 9.4
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.
Many genes have more than two alleles in the population
The alleles for A and B blood types are codominant, and
both are expressed in the phenotype
Blood
Group
(Phenotype)
Genotypes
Antibodies
Present in
Blood
Reaction When Blood from Groups Below Is Mixed with
Antibodies from Groups at Left
O
O
ii
Anti-A
Anti-B
A
IA IA
or
IA i
Anti-B
B
IB IB
or
IB i
Anti-A
AB
IA IB
A
B
AB
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
Geneticists use the testcross to
determine unknown genotypes
The offspring of a testcross often reveal the •
genotype of an individual when it is unknown
TESTCROSS:
GENOTYPES
B_
bb
Two possibilities for the black dog:
BB
Bb
B
GAMETES
b
OFFSPRING
or
Bb
All black
B
b
Bb
b
bb
1 black : 1 chocolate
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.
Genetic traits in humans can be tracked
through family pedigrees
The inheritance of many human
traits follows Mendel’s principles
and the rules of probability
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
Family pedigrees are used to determine patterns •
of inheritance and individual genotypes
Dd
Joshua
Lambert
Dd
Abigail
Linnell
D_?
Abigail
Lambert
D_?
John
Eddy
dd
Jonathan
Lambert
Dd
Dd
dd
D_?
Hepzibah
Daggett
Dd
Elizabeth
Eddy
Dd
Dd
Dd
dd
Female Male
Deaf
Figure 9.8B
Hearing
Many inherited disorders in humans are
controlled by a single gene
Most such •
disorders are
caused by
autosomal
recessive alleles
Examples: –
cystic fibrosis,
sickle-cell
disease
Normal
Dd
PARENTS
Normal
Dd
D
D
Eggs
Sperm
DD
Normal
d
OFFSPRING
d
Dd
Normal
(carrier)
Dd
Normal
(carrier)
dd
Deaf
Figure 9.9A
P GENERATION
aabbcc
AABBCC
(very light) (very dark)
F1 GENERATION
Eggs
Sperm
Fraction of population
AaBbCc AaBbCc
Skin pigmentation
F2 GENERATION
Figure 9.16
Autosomal dominant
disorders
A few are caused by dominant alleles
Examples: achondroplasia, Huntington’s disease
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.
Incomplete dominance results in
intermediate phenotypes
P GENERATION
White
rr
Red
RR
Gametes
R
r
Pink
Rr
F1 GENERATION
1/
1/
Eggs
1/
F2 GENERATION
2
2
2
R
1/
2
r
1/
R
R
Red
RR
r
Pink
Rr
Sperm
1/
Pink
rR
White
rr
Figure 9.12A
2
2
r
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.
Mendel’s principles reflect the rules of probability
F1 GENOTYPES
• Inheritance follows the
rules of probability
– The rule of multiplication
and the rule of addition
can be used to determine
the probability of certain
events occurring
Bb female
Bb male
Formation of eggs
Formation of sperm
1/
B
1/
2
B
2
B
B
1/
b
1/
1/
2
b
4
B
B
1/
b
1/
4
b
1/
b
4
4
2
b
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
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
Autosomal recessive disorder
Aa
Aa
A
a
AA
1
25%
Aa
:
2
50%
A
a
Aa
aa
:
1
25%
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 Inheritance
is complex
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
Sickle cell
Prevalence
1/500 births among African Americans
 Carrier frequency (i.e. prevalence of trait) 8 %
of African Americans

Screening readily accomplished by direct
protein analysis.
 Trait provides resistance to malaria!!.

Old World Malaria prevalence
Sickle cell
Management
1. Crises:
 Oxygen.
 Analgesia.
 May
need transfusions.
2. Long term
 Hydroxyurea,
probably helps prevent polymerization of
hemoglobin (should not be used in pregnant women)
 ? fetal bone marrow transplantation if detected in utero.
 Gene therapy.
 Pneumovax (patients often autosplenectomize).
Cystic fibrosis
Clinical:
Dysfunction of mucous producing glands in gut,
bronchioles, pancreatic exocrine dysfunction and
sweat gland dysfunction.
 Malabsorption, intestinal obstruction.
 Frequent pulmonary obstruction and infections.
 Abnormal vas deferens development  male
sterility.
 Death usually by 20’s from pulmonary
complications.

Hemophilia B
AKA
Christmas disease (After the name of
the first family and publication in the
Christmas issue of the British Medical
Journal)
Similar clinical syndrome as seen in
Hemophilia A
Treatment with plasma or recombinant
factor IX
Antibodies
Caused
develop in 1 to 3 %
by mutations affecting the Factor
IX gene at Xq27
Hemophilia A
Clinical syndrome



Easily prone to hemorrhage from minor trauma
Hemarthroses common - result in degenerative joint disease
Ecchymoses, but not petechiae
Laboratory


Prolonged PTT, normal PT & bleeding times
Normal platelet function
A treatable genetic disease
Plasma (90 % of those treated with donor blood
products developed AIDS in the 1980’s), recombinant
factor 8 (10 -15 % develop antibodies)
Allelic heterogeneity
Over 620 different mutations known to affect the factor
VIII clotting factor gene.
Gene lies at Xq28
A nicer pedigree
A high incidence of hemophilia has plagued the •
royal families of Europe
Queen
Victoria
Albert
Alice
Louis
Alexandra
Czar
Nicholas II
of Russia
Alexis
Figure 9.23B
Thalassemias



A group of hemoglobinopathies primarily characterized by
abnormal levels of a particular globin chain.
More prevalent in malaria endemic regions; trait may
provide resistance to malaria.
-thalassemias: Reduced levels of -globin.
 2 -globin genes on chromosome 16, therefore normally
4 -globin genes in human genome.
 When 2 -globin genes are inactive: -thalassemia trait
 When 3 -globin genes are inactive: detectable 4 (HbH),
with significant but non-lethal anemia.
 When all 4 -globin genes are inactive: 4 (Hemoglobin
Bart’s) predominates leading to hydrops fetalis, neonatal
or fetal lethal anemia with widespread tissue necrosis.
Thalassemias
Location: -globin gene lies on chromosome 11
•Huge
range of mutation types, leading to reduced
levels of -globin gene expression from affected
chromosome
•Heterozygotes unaffected
•Homozygous state: First year of life relatively
normal since fetal hemoglobin still present, as fetal
globin declines and attempts to make adult globin
commence, anemia develops with massive
hepatosplenomegaly, marrow space enlargement
Management:
Transfusions, but must combine with iron
chelation to prevent iron deposition and
hemochromatosis
?Bone marrow transplantation
Management

Transfusions, but must combine with iron
chelation to prevent iron deposition and
hemochromatosis

?Bone marrow transplantation
X-linked inheritance
Sex-linked disorders affect mostly males
• Most sex-linked human
disorders are due to
recessive alleles
– Examples: hemophilia,
red-green color blindness
– These are mostly seen in males
– A male receives a single X-linked allele from his
mother, and will have the disorder, while a female
has to receive the allele from both parents to be
affected
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
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:
G6PD deficiency
 Affects
the G6PD gene at Xq28.
 Many
mutations and polymorphisms have
been discovered.
 Heterozygosity
(technically hemizygosity) in
women appears to confer resistance to
malaria.
Glucose-6-phosphate dehydrogenase deficiency



Common among Africans, Asians and around
the Mediterranean
Discovered that about 10 % of African American
servicemen during WWII developed hemolytic
anemia when given certain drugs, such as
sulfonamides, antimalarials or when they ate
fava beans
Caused by deficiency of the enzyme, which is
needed to generate NADPH
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
Y-linked traits
Affects only males, carriers usually express
the trait
 Passed directly from father to son


About 3 dozen Y-linked traits have been
discovered.
Mitochonrial disorders

Passed directly from an affected mother to
all offspring.

Only females pass trait on.
Variation in expression
Penetrance
The frequency of expression of an allele
when it is present in the genotype of the
organism (if 9/10 of individuals carrying an
allele express the trait, the trait is said to be
90% penetrant)
Expressivity
Variation in allelic expression when the allele
is penetrant.
Hound Dog Taylor
Expresses polydactyly
Prevalence of G6PD
A famous pedigree
A modest pedigree
Clotting cascade
One common Factor VIII mutation