Download Patterns of Inheritance of Genetic Disease

Pathophysiology
101-823
Unit 2
Genetics & Genetic Disease
Patterns of Inheritance of
Genetic Disease
Paul Anderson
2017
Learning Objectives
1.  Explain Mendelian inheritance of genetic traits in humans (Law of Segregation & random
fertilization).
2.  Define: homozygous, heterozygous, carrier, dominant recessive, genotype, phenotype.
3.  Use a Punnett square to show expected offspring of single gene disorders & interpret a
pedigree chart.
4.  Describe the inheritance pattern of Autosomal Recessive traits, Autosomal Dominant traits &
Sex (X) Linked conditions in humans with examples.
5.  Describe the inheritance & manifestatons of Huntington Disease; describe the inheritance
pattern of Myopia & Hereditary Retinoblastoma (Retinoblastoma Susceptibility).
6.  Describe the inheritance, phenotype & manifestations of cystic fibrosis, Tay Sachs, Albinism
& PKU; for PKU describe screening & treatment: for CF describe basic pathophysiology.
7.  Define Incomplete Dominance & describe the inheritance of Sickle Cell Anemia (Sickle Cell
Disease) & Familial Hypercholesterolemia.
8.  Define codominance & describe the inheritance of the human blood types A, B, AB & O.
9.  Describe the inheritance pattern, major manifestations & treatment of Hemophilias.
10. Describe the risk factors and manifestations of Schizophrenia; explain why it is considered to
be multifactorial.
References:
Martini & Bartholomew, Essentials of Anatomy & Physiology,7th ed. Ch. 20, pp. 695-698
Porth, Pathophysiology, 2nd Can. ed. Ch. 6, pp. 133-135: Ch. 7, pp. 141-147
Ch. 53, pp. 1385-1386, (Schizophrenia, pp. 1393-1396), (Huntington, pp. 1409):
Ch. 54 Retinoblastoma, pp. 1342-1343.
Porth, Essentials of Pathophysiology, 4th ed., Ch.5, pp. 98-99: Ch. 6, pp. 107-114: Ch. 7, p.138.
Mendelian Genetics
•  Modern genetics began in
about 1857 when a Czech
Monk - Gregor Mendel began
studying inheritance in pea
plants.
•  Mendel used peas to study
how inherited traits passed
from parent to offspring.
•  Mendel was the first person
to discover the basic rules
for genetics.
Genetically different pea plants
Mendel’s Law of Segregation
•  For each inherited trait an individual has 2 factors
(now called genes) one inherited from each parent.
•  The 2 factors may be the same or different.
• The 2 factors separate
out (or segregate) in
forming gametes so
that each gamete has
only one factor)
Diploid
Parent
Cell
Haploid
gametes
We now know that:
•  Mendel’s factors are genes.
•  Genes exist as alternate forms called alleles.
•  Genes are carried on chromosomes which segregate in Meiosis I
forming haploid gametes from a diploid parent cell.
We Inherit One Copy of a Gene from Each Parent
We now know that:
•  Haploid gametes carry
one copy of each gene.
• Fertilisation between
haploid gametes restores
the diploid number of
chromosomes with two
copies of each gene.
One set of
genes from
Mother
One set of
genes from
Father
Haploid
gametes
Diploid
Zygote
Offspring
inherits two
sets of genes
Dominant & Recessive Alleles
•  Alleles are alternative versions of a gene (e.g. alleles for normal
skin colour or for albinism).
•  New alleles are originally formed by gene mutations but usually
we inherit them from our parents.
•  Mendel discovered that some alleles (Mendel -“factors”) are always
expressed, i.e. produce a visible result: we call these dominant
alleles.
•  Mendel discovered that other alleles are only expressed when two
are inherited: we call these recessive alleles.
Dominant alleles are symbolised in upper case,
Recessive alleles with lower case.
Examples:
A allele for normal skin colour (dominant)
a allele for albinism - absence of skin colour (recessive)
Genotype vs Phenotype
•  The particular combination of alleles an individual has is referred to
as the individual’s genotype
•  The genotype is symbolised with gene symbols, e.g. AA, Aa or
aa.
•  The visible expression of genes in an individual is referred to as the
phenotype, e.g. albino or normal skin colour.
The genotype and phenotype may differ.
•  A person who has two identical alleles is homozygous &
both genes will be expressed in the phenotype,
e.g. AA (normal skin colour) or aa (albino)
•  A person who has two different alleles is heterozygous,
e.g. Aa & only the dominant allele (normal skin colour) will be
expressed in the phenotype.
•  The heterozygote for recessive traits is called a
carrier since the person does not show the trait but can
transmit it to offspring.
Use of Punnett Squares
Mendel discovered that
Heterozygous parents
•  Fertilisation is a random
process.
•  The proportion of
different offspring
could be predicted
based on laws of chance
(probability).
This can be shown by a
Punnett Square which
combines the gametes
from each parent in all
possible combinations.
Dd
Dd
1/2
D
1/2
d
sperm
Homozygote Heterozygote
dominant
D
DD
Dd
Heterozygote
Homozygote
recessive
1/2
ova
1/2
d
Dd
dd
offspring
Genetic Disorders (Disease)
Genetic Disorders are caused by inherited gene
mutations or chromosomal mutations.
Gene
Mutations
Single Gene
Disorders
Multifactorial
Disorders
Genetic
Disorders
Chromosome
Mutations
Crossover
errors
Non
Disjunction
Single Gene Disorders
About 8000 Single Gene Disorders are known, caused by a
mutation to a single gene: most follow one of three patterns.
• Autosomal Dominant Disorders: the allele for the disorder is
on an autosome & is dominant. Examples:
- Huntington Disease
- Risk for Hereditary Retinoblastoma
- Familial Hypercholesterolemia
- Myopia
• Autosomal Recessive Disorders: the allele for the disorder is
on an autosome & is recessive. Examples:
- Enzyme Deficiency Diseases (e.g. albinism, PKU, Tay Sachs)
- Cystic Fibrosis
- Sickle Cell Disease
- Xeroderma Pigmentosum
• X Linked Recessive Disorders: the allele for the disorder is on
the X chromosome & is recessive. Examples:
- Hemophilias
- Colour Blindness
Using Pedigrees to Determine Genetic Patterns
• A pedigree is a chart used to determine the pattern
of inheritance for human genetic traits.
• A pedigree is a family tree showing known phenotypes
for any given genetic trait, generation by generation.
• Males are shown by squares, females by circles and
individuals with the trait in question are shaded.
Carriers for recessive traits may also be identified.
•  Autosomal disorders appear with
equal frequency in males and
females.
•  Identify the genetic pattern
shown by this pedigree.
Autosomal
(could be dominant or recessive)
Hh
Hh
hh
hh
Hh
Hh
Most likely a
Dominant trait
hh
Hh
hh
Hh
hh
Characteristics of Autosomal Dominant Disorders
•  In Autosomal Dominant Disorders only one allele needs
to be present for the disorder to show.
•  Dominant disorders show a “gain” in abnormal function
due to the presence of the mutated gene’s protein.
• Huntington Disease (HD or Huntington’s Chorea) is a
rare (1 in 10,000) degenerative fatal neurological
disorder caused by a dominant autosomal allele.
• HD like many other neurodegenerative diseases
(Alzheimers, Parkinson, ALS) causes a misfolding of a
brain protein.
• In HD the abnormal protein huntingtin builds up &
prevents other proteins from breaking down.
• Build up of proteins causes cellular injury and death.
• HD is a brain disorder with atrophy of basal ganglia &
frontal cortex.
Manifestations of Huntington Disease
•  HD is typically delayed onset (appears in late 30s– 40s).
•  Early signs of HD are depression, personality changes,
clumsiness and slurred speech.
•  This is followed by progressive, uncontrolled patterns of
involuntary movements especially of hands, face eyes
and tongue (chorea).
•  Psychological (cognitive) deterioration follows leading to
dementia.
•  Chorea is replaced by akinesia (absence of movement)
and eventually rigidity.
•  Patients may live for further 10-20 yrs after onset of
signs & usually die from infections.
•  HD allele is at tip of chromosome 4 so (since 1993)
DNA can be directly tested before signs appear.
Inheritance of Huntington Disease
Typical Pattern
of Inheritance
Affected parent Hh
h
H
Normal
Parent
hh
h
Hh
hh
h
Hh
hh
1/2 children affected
Woody Guthrie
1912 - 1967
Rules for Dominant Autosomal Traits
•  A dominant trait will not appear among offspring unless it also
appears in one or both parents.
•  When a dominant trait is rare in a population most affected
persons are heterozygotes. Therefore if one parent has the
trait typically half the children will be affected (e.g.
Huntington).
•  Dominant traits may show variable penetrance (some
individuals with the dominant allele do not show the trait).
•  Huntington Disease has a high penetrance (close to 100%) so
risk of a person with Huntington allele getting the disorder is
very high & it does not “skip” generations.
•  Dominant traits may show variable expressivity (allele can be
expressed differently in phenotypes).
•  In Huntington Disease some affected persons show dementia,
others do not.
Pedigree for Huntington Disease
Myopia: A Dominant Autosomal Trait
Early Onset Myopia, or Near Sightedness, is an autosomal
dominant condition in which distant rays of light converge
before striking the retina, causing blurred vision. However,
the myopic person can see near objects clearly.
• Myopia is caused by
a lens which is too
convex, or an eyeball
which is too long.
• The condition may be
corrected with
concave lenses or by
radial keratotomy
which surgically (or
using laser) alters
corneal curvature.
Inheritance of Retinoblastoma Susceptibility
•  Retinoblastoma is a rare type of eye cancer in infants caused by a
gene mutation on the RB gene on chromosome 13.
•  RB is a Tumor Suppressor gene: its protein product stops the cell
cycle of DNA damaged cells at G1. A recessive gene mutation forms an
abnormal protein that it is unable to regulate cell division.
•  Two mutations (one on each homologue) are necessary to cause RB.
•  In 50% of RB cases a single inherited (germline) mutation gives an
increased risk of developing Inherited Retinoblastoma, an autosomal
dominant pattern for Retinoblasoma Susceptibility.
For Retinoblastoma to
develop, a second somatic
mutation must occur in
the other copy of the RB1
gene in retinal cells during
the person's lifetime
(“Two - Hit Hypothesis
for cancer”).
Increased risk
Porth fig. 8-6.
Porth Essentials fig. 5-7
Autosomal Recessive Disorders
• Recessive disorders show a “loss” of normal function of
the mutated gene’s protein, e.g. “Enzyme Deficiency
Diseases” or “Inborn Errors of Metabolism”.
• In most Autosomal Recessive DisordersThe normal allele
is completely dominant so heterozygotes appear normal.
• However, even with Complete Dominance the
heterozygote produces 50% of the normal protein so
carriers of recessive disorders can be identified
biochemically.
• Tests for deficiency of the gene product (an enzyme)
can now identify carriers of PKU and Tay Sachs* (both
Recessive Enzyme Deficiency Disorders).
*Tay Sachs is a fatal childhood disorder affecting the brain & retina caused by the absence
of a lysosomal enzyme that catabolises lipids. Accumulation of lipids causes mental & motor
deterioration by 10 months with increasing flaccidity, seizures & eventual blindness.
Recessive Autosomal Traits: Albinism
• Albinism is a homozygous recessive trait resulting in enzyme
deficiency which causes suppression of normal production of the dark
melanin pigment in the skin, hair and iris.
•  Albinos are very sensitive to sunlight and so must avoid exposure and
be screened for malignant changes in the skin and eyes.
Typical Pattern of Inheritance
Both Parents non- affected carriers Aa
A
a
A
AA
Aa
a
Aa
aa
1/4 children affected
Child with albinism
Rules for Recessive Autosomal Traits
• Recessive Traits commonly "skip" a generation affected child can be born to non - affected parents
so frequency of affected individuals in a pedigree is
usually small.
• If two unaffected) parents have an affected child it
will only occur 25% of the time.
• When two recessive (affected) individuals have
children they are all affected.
• Autosomal Recessive disorders tend to be early onset
with uniform clinical manifestations.
• The protein deficiency in autosomal recessive
disorders often causes multiple phenotypic effects.
Pedigree for Albinism!
Inheritance of Phenylketonuria (PKU)
• PKU is an Autosomal Recessive Disease with an
incidence of 1 in 10,000-15000 births.
• PKU is caused by absence of the hepatic enzyme
phenylalanine hydroxylase (PAH) which normally
converts one amino acid (phenylalanine) to another
(tyrosine) by adding –OH.
• PKU is thus an Enzyme Deficiency Disease or “Inborn
Error of Metabolism”.
• A child can inherit the disease from normal parents
who are heterozygous carriers.
Manifestations of Phenylketonuria (PKU )
• In PKU there is an increased concentration of
phenylalanine (substrate for PAH).
• Excess phenylalanine is converted by the liver to
phenylpyruvic acid (a phenyl ketone).
• Phenylalanine & Phenylpyruvic acid reach high levels in
blood, toxic to developing brain of infant, causing
severe mental retardation, microcephaly, delayed
speech etc.
• In PKU decreased concentration of the product for
PAH (tyrosine) leads to deficiency of the skin pigment
melanin (so less colour in hair, skin, iris).
Metabolism in PKU Disease
Diet
Hepatic Enzyme missing in PKU
Phenylalanine
Pathway
in PKU
Phenylpyruvic
acid
Brain
toxic to
developing
brain
↓IQ ↓Development
Low IQ & poor brain
development in PKU
Enzyme
Phenylalanine
hydroxylase
(PAH)
Tyrosine
Normal
Pathway
melanin
normal skin,
hair, eye colour
reduced in PKU
Urine
(Phenylketonuria)
Screening & Treatment for
Phenylketonuria (PKU )
• Phenylalanine & phenylpyruvic acid can be
detected in blood & urine (“phenylketonuria”) of
affected newborns.
• Newborns are routinely screened for PKU from a
few drops of blood from the heel within the first
72 hrs.
• Carriers of PKU have 50% of the normal enzyme
so can be detected via a test that measures
how quickly an oral phenylalanine dose is
metabolised & disappears from the blood.
• Treatment for PKU consists of a phenylalanine
reduced diet for life & must begin by 10 days
after birth.
Genetics of Cystic Fibrosis
• Cystic Fibrosis is the most
common lethal genetic disease in
Caucasians affecting 1 in 2500
with 1 in 25 (4%) being carriers.
•  Typical of recessive disorders CF
shows early onset, appearing soon
after birth.
•  The Allele for CF (Cystic Fibrosis)
is on chromosome 7: the most
common mutation is a codon
deletion (one amino acid –
phenylalanine missing).
•  DNA Mutation analysis can be
used for prenatal diagnosis and
for carrier testing in families with
a previously affected child.
N:Normal allele
C: Cystic Fibrosis allele
Like other recessive disorders
2 carriers (NC) have a 1/4
chance of a child with CF.
Basic Pathophysiology of Cystic Fibrosis
•  The CF gene codes for a chloride
channel membrane protein (CFTR*).
•  The CF allele results in decreased
chloride transport across mucosal
epithelial cells.
•  Failure of epithelial cells to
transport chloride results in
- sticky, viscous mucus
secretions in respiratory
tract, pancreas, GI tract and
other exocrine tissues.
- excessively salty sweat
•  More viscous mucus may lead to
obstructions in respiratory and
digestive systems and impaired
pancreatic function.
*CFTR: Cystic Fibrosis Transmembrane Regulator.
Incomplete Dominance
•  In some single gene disorders one allele shows Incomplete
Dominance over the other allele so the heterozygote shows an
intermediate phenotype (milder form of disorder).
•  Examples of Incomplete Dominance include
- Sickle Cell Disease (recessive)
- Familial Hypercholesterolemia (dominant).
• Familial Hypercholesterolemia is a primary (inherited) form of
hypercholesterolemia caused by a mutation in the gene for LDL
receptor proteins in cell membranes (mainly the liver).
•  LDL carries “bad cholesterol” so as a result cells with defective LDL
receptors cannot take in LDL and blood cholesterol levels stay high.
•  Heterozygote (LDL cholesterol <13 mmol/L) shows delayed onset
disease, & usually has heart attack before 40 years.
•  Homozygote child (LDL cholesterol <26 mmol/L) may have heart attack
before 2 years of age.
Sickle Cell Anemia
•  Sickle Cell Anemia is an autosomal recessive disease
in which the recessive allele causes a single amino
acid substitution in the beta chains of hemoglobin.
•  Homozygous recessives form abnormal hemoglobin
which causes sickling of red cells when oxygen
concentration is low (e.g. with activity)
•  Hemolysis of the abnormally shaped fragile
erythrocytes cause a severe hemolytic anemia with
circulatory blockages which shorten the life span.
•  The normal allele shows Incomplete Dominance so
Heterozygotes are phenotypically normal but have a
mixture of the 2 Hbs and may develop a mild
anemia at low O2 levels (Sickle Cell Trait).
•  On a molecular level each allele produces its protein
product (i.e. normal or sickle cell hemoglobin) in the
heterozygote.
Genetics of Sickle Cell Anemia
•  10 % of African Americans are heterozygous, while
only 0.2% are homozygous recessive.
• Usually a child with sickle cell disease is born to 2
heterozygous carriers with Sickle Cell Trait who have
a 1/4 chance of having a child with Sickle Cell Anemia.
Phenotypes
Normal SS
Sickle cell Trait
Ss
Sickle cell Anemia
ss
S
s
S
s
1/4 ss
Inheritance of Human Blood Types
• Codominant alleles are dominant alleles that are fully expressed
in the HETEROZYGOTE when both are present.
•  The major Human Blood Types (A, B, AB and O) are caused by
the inheritance of 2 codominant alleles A and B and a third recessive
allele O at the same locus giving 6 possible genotypes & 4 phenotypes.
•  Each codominant allele A or B causes the production of polysaccharide
antigens (A or B) on the surface of erythrocytes whereas the type O
individual (double recessive) has neither A nor B antigens.
Genotypes
AA or AO
Phenotypes;
Type A
BB or BO
Type B
AB
Type AB
OO
Type O
A
O
B
A B
B O
O
A O
O O
Complete the Punnett square for a man
of type A & a woman of type B, each of
whom had a parent of type O.
Sex (X) Linked Disorders
•  Sex Linkage refers to the pattern of inheritance for
genes carried on the sex chromosomes (usually the X).
•  Each X chromosome carries ~1,200 genes, whereas Y
is non - homologous & contains fewer (231) genes.
•  Males have only one allele for each X linked gene so X
linked disorders are more common in males (male
genotype is hemizygous).
•  Males inherit the trait from their
mother who is usually an
unaffected carrier.
•  If the mother has the disorder all
sons will be affected.
•  Daughters inherit the disorder
from both parents.
•  Males transmit the trait to
daughters only.
X
Y
X X
XY
X X X
XY
X
Location of Genes for X - Linked Disorders
X Chromosome
Porth fig. 6-12.
Porth Essentials fig. 3-9
Hemophilias
hemophiliac allele: Xh
normal allele: XH
• X linked disorders include
hemophilias, blood clotting disorders
caused by an inability to produce a
specific protein clotting factor by the
liver
• In Hemophilia A factor VIII is missing
or deficient: incidence 1/5000 of male
births.
• In severe cases internal bleeding occurs
in childhood especially in GI tract &
joints (when child first walks).
• Treatment involves replacing missing
factor VIII by intravenous injection.
• 30% of cases have no family history so
are new (somatic) mutations.
Y
XH
XH
XH XH XH Y
Xh
Xh XH
Xh Y
Usual Pattern
•  Mother a carrier:
father normal
•  Half sons hemophiliac
•  Half daughters are
carriers
Note: males are hemizygous for sex linked genes
Hemophilia in the Royal Families of Europe
Multifactorial Inheritance
•  Many human genetic traits are controlled by the
interaction of many non - allelic genes (called
polygenes) at different loci.
•  Polygenes are affected by environmental influences
such as nutrition, hormones, prenatal environment etc.
so these traits are also called multifactorial.
•  Multifactorial Inheritance in adults involve an
inherited genetic predisposition for such traits as
o height
o Weight
o athletic ability
o IQ
o Disorders such as hypertension, CHD, diabetes type 2
and Schizophrenia.
Manifestations of Schizophrenia
• Schizophrenia is a delusional psychotic disorder (often
with hallucinations) first appearing usually in young
adults (17-25).
• Schizophrenia affects thought and language causing
delusions, disorganised (incomprehensible) speech, visual
and auditory hallucinations and sometimes catatonic
behaviour (state of apparent inertia or stupor with
muscle rigidity.
• Positive symptoms of schizophrenia include delusions or
false beliefs, hallucinations, abnormal perceptions
without external stimuli.
• Negative symptoms of schizophrenia include apathy,
withdrawal and lack of emotions.
Multifactorial Inheritance & Schizophrenia
• Schizophrenia is associated with disturbed
neurotransmitter activity (e.g. increased
dopamine receptors in the basal ganglia) with
anatomical & functional changes in the
forebrain.
• Schizophrenia risk is increased by 10x if there
is an affected close family member so has a
strong genetic component.
• Cannabis use in young adults often triggers the
first psychotic episode so is now considered a
risk factor (increases risk 3x).