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INTRODUCTION to MEDICAL GENETICS

MONOGENIC DISORDERS

GENETIC DISORDERS
A. Etiology
- all are a result of a mutation in the genetic code
1. Point Mutation
- change of a single base-pair of a gene → incorporation of incorrect amino acid →
functional change in the product protein (ex: thalassemia)
2. Frameshift Mutation
3. Recombination Event Errors
- gross rearrangement of the gene/errors in chromosome movement (ex: chronic
myeloid leukaemia)
B. Types
1. Congenital
- inherited at birth
2. Somatic
- arise during a person’s life
- responsible for the collective disease known as cancer
- gross chromosomal and point mutations occur in somatic genetic disease
C. Major Categories
1. Single Gene (Monogenic) or Mendelian Defects
2. Multifactorial Disorders
3. Chromosomal Disorders
4. Somatic Cell Gene Defects
5. Mitochondrial Mutations
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GENE DEFECTS
A. Mendelian and Sex-Linked Single-Gene Disorders
- result of mutations in coding sequences and their control elements → various effects on gene
expression → dysfunction of protein product
B. Mutations
1. Point mutation
- simplest type of change
- involves substitution of one nucleotide for another → changed codon in a coding sequence
a. Thalassemia
- different amino acids are incorporated into the polypeptide chain
2. Insertion or Deletion
- more serious change → alteration of the rest of the following sequence → frame-shift
mutation
a. Duchenne Muscular Dystrophy
- large deletions in the dystrophin gene
b. Insertion/Deletion (ID) Polymorphism in the Angiotensin-Converting Enzyme (ACE)
Gene
- deletion of 287 bp repeat sequence
- result in the genotypes II (ID and DD)
- DD - associated with
- higher concentrations of circulating ACE
- possibly cardiac disease
3. Splicing Mutations
- mutation of DNA sequences which direct the splicing of introns → abnormal splicing →
mRNA may carry intron sequences → translation → altered polypeptide chain
4. Termination Mutations
a. Normal Polypeptide Chain Termination
- when the ribosomes processing the mRNA reach one of the chain termination or “stop”
codons
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b. Termination Mutations
→ late or premature termination
- ex: Haemoglobin Constant Spring
- hemoglobin variant
- instead of “stop” sequence → single base change → insertion of extra amino
acid

c. The Copy Number Variation Project

- investigate large pieces of DNA between 10 thousand and 5 million letters (copy
number variation) in the hope of identifying diseases that may be associated
with this type of mutation
C. Single Gene (Monogenic) Defects
- result from a mutation at a single site (gene) on a chromosome
- inherited in a simple Mendelian pattern
- number more than 6000
- incidence of about 1 in 200 births
1. Classic Divisions
a. Recessive Pattern of Inheritance
- usually seen with enzyme deficiencies
i. Heterozygote for a Recessive Disorder
- the normal gene provides sufficient enzyme to prevent clinical symptoms
- generally “normal”
ii. Homozygote for a Recessive Disorder
- receive 2 defective genes (1 from each parent)
- shows clinical symptoms
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b. Dominant Pattern of Inheritance
- commonly seen with defective structural proteins → disrupt physiologic structures →
disastrous effect on function
i. Heterozygote for a Dominant Disorder
- 1 normal and 1 defective gene
- exhibit disease symptoms

c. X-Linked

2. Multiple Forms of Inheritance Pattern

- in many syndromes
- multiple defects can occur within a given disease-associated gene or in separate genes which
all contribute to a particular molecular/cellular pathway and thus give rise to the same
phenotype
- ex: Ehlers-Danlos Syndrome
- autosomal dominant, recessive and X-linked inheritance
Factor V Leiden Disease
- boundary between dominant and recessive forms is very blurred
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3. Racial or Geographical Prevalence
a. Thalassemia
- seen mainly in
- Greeks
- South East Asians
- Italians
b. Porphyria Variegata
- more frequently in the South African white population
c. Tay-Sachs Disease
- Ashkenazi Jewish people
d. Cystic Fibrosis
- most common recessive disease in the UK
4. Pedigree Nomenclature

5. Autosomal Dominant Disorders

- relatively rare in populations
- males and females are affected in roughly equal frequencies
- each diploid cell contains two copies of all the autosomes
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a. Occurrence
- occurs when one of the two copies has a mutation and the protein product of the
normal form of the gene cannot compensate
- a heterozygous individual who has two different forms (or alleles) of the same
gene → manifest the disease
- offspring of heterozygotes → 50% chance of inheriting the chromosome
carrying the disease allele → disease
- affected persons may be of both sexes
- appear in most generations
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b. Estimation of Risk to Offspring
i. Recurrence Risk for the Mating of an Affected Individual (Aa) with a
Homozygous Unaffected Individual (aa)

Disease allele is A, recurrence risk is 50%

c. Factors That Makes Difficult the Estimation of Risk to Offspring

- for counselling families
i. Great Variability in Manifestation
ia. Incomplete Penetrance
- if patients have a dominant disorder but it does not manifest
clinically (gene having “skipped” a generation)
ii. Variable Expression
- dominant traits are extremely variable in severity
- occurs when the severity and nature of the disease phenotype varies between
individuals with the same mutant genotype
- a mildly affected parent may have a severely affected child
iii. New Mutation
- new cases in a previously unaffected family may be the result of a new
mutation
- risk of a further affected child is negligible
- recurrence risk for future offspring of diseased individual follow normal
patterns
- ex: 80% of achondroplasia
50% of neurofibromatosis type 1
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iiia. Achondroplasia
- most cases are due to new mutations

A child with Achondroplasia

- rhizomelic shortening
- radiograph of the pelvis in a child with Achondroplasia
- squared-off iliac wings
- flat and irregular acetabular roofs
- thick femoral necks
- ice-cream-scoop-shaped femoral heads

iiib. Neurofibromatosis Type 1

d. Overall Incidence
- 7 per 1000 live births
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e. Huntington Disease
- autosomal dominant
- 1 in 20,000
- manifestations
- progressive dementia
- loss of motor control
- affective disorder
- trinucleotide repeat expansion disorder
- buildup of toxic protein in neurons results in neuronal death
f. Marfan Syndrome
- autosomal dominant
- 1 in 10,000
- mutation in fibrillin gene
- manifestations
- thin
- elongated limbs
- hypermobile joints
- frequent myopia
- mitral valve prolapse
- aortic aneurysm
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6. Autosomal Recessive Disorders
- manifest only when an individual is homozygous for the disease allele (both chromosomes
carry the mutated gene)
- affected persons are of both sexes
- appear sporadically and infrequently throughout a family tree
- typically seen in only one generation of a pedigree
- males and females are affected in roughly equal frequencies

a. Family History
- parents are generally unaffected healthy carriers (heterozygous for the disease allele)
- usually no family history
- defective gene is passed from generation to generation
b. Offspring of an Affected Person
- healthy heterozygotes unless the other parent is also a carrier
i. Recurrence Risk for the Mating of Two Heterozygous Carriers (Aa) of Recessive
Mutation

Disease allele is a, recurrence risk is 25%

c. Carriers
- if marries → offspring have
- 1 in 4 chance of being homozygous and affected
- 1 in 2 chance of being a carrier
- 1 in 4 chance of being genetically normal
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d. Consanguinity
- increases the risk
e. Clinical Features
- usually severe
- often present in the first few years of life
- high mortality
f. Overall Incidence
- about 2.5 per 1000 live births
7. Sex-Linked Disorders
a. Genes on the X Chromosome
- said to be “X-linked”
- can be dominant or recessive
i. Females
- have two X chromosomes → unaffected carriers of X-linked recessive
diseases
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ii. Males
- have just one X chromosome → any deleterious mutation in X-linked gene →
manifests because no second copy of the gene is present
b. X-Linked Dominant Disorders
- rare
i. Who Will Manifest the Disease
- females who are heterozygous for the mutant gene
- males who have one copy of the mutant gene on their single X chromosome
- half the male or female offspring of an affected mother
- all the female offspring of an affected man will have the disease
ii. Affected Males
- has only one X chromosome → always passes the disease to daughters
- tend to have the disease more severely than the heterozygous female

iii. Recurrence Risks for X-linked Dominant Diseases

Affected Male
X Y
x Xx xY
x Xx xY
Normal Female

Normal Male
x Y
X Xx XY
x xx xY
Affected Female
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iv. Example Diseases
iva. Hypophosphatemic Rickets
ivb. Fragile X Syndrome
ivbi. Males
- 100% penetrance
- mental retardation
- large ears
- prominent jaw
- macro-orchidism (usually postpubertal)
ivbii. Females
- 60% penetrance
- mental retardation
c. X-Linked Recessive Disorders

i. Who Will Manifest the Disease

ia. Males
- carry one X chromosome (hemizygous) that is always inherited
from the mother
- have only one allele for each gene on the X-chromosome →
recessive mutant gene is always expressed
ib. Homozygous Females
- usually rare
ic. Manifesting Heterozygotes
- heterozygous female occasionally express X-linked recessive
mutation because (X chromosomes carrying the normal allele
may have been inactivated)
- disease expression is typically milder than hemizygous males
id. Skipped Generations
- commonly seen
- affected male transmit the disease-causing mutation to a
heterozygous daughter (who is unaffected but who can
transmit the disease-causing allele to her sons)
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ii. Transmission
- by - healthy female carriers
- affected males if they survive to reproduce
- male-to-male transmission is not seen
iii. Recurrence Risks for X-linked Recessive Diseases

Affected Male
x Y
X Xx XY
X Xx XY
Normal Female

Normal Male
X Y
X XX XY
x Xx xY
Carrier Female

iv. Hemophilia A
iva. Defect
- mutation in the X-linked gene for factor VIII
- intrachromosomal rearrangement (inversion) of the tip of the long
arm of the X chromosome (one break point being within
intron 22 of the factor VIII gene) in 50% of cases
ivb. Offspring from a Carrier Female and a Normal Male
- 50% of the girls → inherit a mutant allele from their mother and the
normal allele from their father → carriers
- 50% of the girls → inherit two normal alleles → normal
- 50% of the boys → inherit the mutant allele from their mother (and
the Y chromosome from their father) → hemophilia
- 50% of the boys → inherit the normal allele from their mother (and
the Y chromosome from their father) → normal
ivc. Male Offspring of a Male with Hemophilia and a Normal Female
- do not inherit his X chromosome → will not have the disease
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ivd. All Female Offspring of a Male with Hemophilia and a Normal Female
- inherit his X chromosome → carriers
v. Other Example Diseases
- Duchenne muscular dystrophy
- Lesch-Nyhan syndrome (hypoxanthine-guanine phosphoribosyltransferase
[HGPRT] deficiency)
- glucose-6-phosphate dehydrogenase deficiency
- hemophilia A and B
- red-green color blindness
- Menke’s disease
- ornithine transcarbamoylase (OTC) deficiency
- SCID (IL-receptor γ-chain deficiency)
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d. Incomplete Penetrance
- some individuals who have the disease genotype do not display disease phenotype
- “degree of penetrance” is the proportion of obligate carriers who display the
disease phenotype
- these are diseases in which a secondary event is required to cause expression

i. Diseases Exhibiting Incomplete Penetrance

ia. Retinoblastoma
- one copy of mutant tumor suppressor gene inherited
- second copy must be knocked out during individual’s lifetime
ib. Familial Breast Cancer
- BRCA1 or BRCA2 inherited
- second hit required
ic. Hereditary Hemochromatosis
- autosomal recessive
- 1 in 300 whites
- excessive iron stores
e. Y-Linked Genes
- genes carried on the Y chromosome → Y-linked
- only males can be affected
- no known examples of Y-linked single-gene disorders which are transmitted
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8. Sex-Limited Inheritance
- occasionally a gene can be carried on an autosome → manifests itself only in one sex
a. Frontal Baldness
- autosomal dominant disorder in males
- behaves as a recessive disorder in females
9. Determining the Mode of Inheritance in a Pedigree
10. Other Single-Gene Disorders
- may be due to mutations in single genes but do not manifest as simple monogenic disorders
- variety of mechanisms
a. Triplet Repeat Mutations
i. Dystrophia Myotonica
- mutated allele found to have an expanded 3’-UTR region (three nucleotides,
CTG, repeated up to about 200 times)
- some mechanism during meiosis → triplet repeat expansion → offspring
inherit an increased number of triplets
- number of triplets affects mRNA and protein function
ia. Late-Onset Form
- had 20-40 copies of the repeat
ib. Early-Onset Form
- children and grandchildren who presented with the disease from birth
had vast increases in the number of repeats, up to 2000
copies
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b. Mitochondrial Diseases
- various mitochondrial gene mutations → complex disease syndromes with incomplete
penetrance maternal inheritance
i. Mitochondria
- carry their own DNA
- inherited from the mother (only the oocyte contributes mitochondria to the
zygote; the sperm neck and tail, which carry mitochondria of the sperm,
never penetrate the oocyte)
ii. Maternal Mitochondria Mutation
- any mutation → passed to offspring
- heterogenous mitochondrial DNA → often a defect in one or many
mitochondria can be compensated for by others → not all mutations
cause disease

iii. Leber Hereditary Optic Neuropathy

- mitochondrial DNA codes for proteins important in electron transport and
oxidative phosphorylation
- mutations for these proteins affect cells which have high-energy
requirements
- irreversible loss of vision in the central field begins in the third decade
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c. Imprinting
- modification of a gene’s ability to be expressed
- maintained in all somatic cells of the offspring
- involves methylation and possibly other mechanisms to imprint or inactivate the
appropriate loci other than changing the base sequence of the DNA
- imprintable alleles are transmitted in Mendelian fashion
- relevant to human genetic disease because different phenotypes may result depending
on whether the mutant chromosome is maternally or paternally inherited
- occurs when identical genes are expressed differently, depending on which parent
they are inherited from
- occurs in specific loci on several chromosomes
- expression of the gene will be determined by the sex of the parent
a. Maternal Imprinting
- alleles that females modify during gamete formation which may
never be expressed in their children
- eggs made → certain alleles marked (ex: methylation of adenine or
cytosine bases in CpG islands in the genes’ promoter) →
genes not expressed when the egg is fertilized (and in all
progeny cells)
- corresponding paternal allele is not inactivated during maternal
imprinting
- if the father has inactivating mutation in a maternally imprinted gene
→ fetus lack expression of that gene (maternal gene
imprinted, paternal gene mutated) → disease
- 50% probability of passing the mutated allele to children (father has
one normal gene, one mutated allele at the imprinted locus)
b. Paternal Imprinting
- alleles that males modify during gamete formation which may never
be expressed in their children
i. Deletion of Part of the Long Arm of Chromosome 15 (15q11-q13)
→ Prader-Willi syndrome (PWS) if it is paternally inherited
→ Angelman’s syndrome (AS) if it is maternally inherited

ia. Affected Gene

- maternal chromosome 15 UBE3A → ubiquitin ligase
- expressed in the
- brain
- hypothalamus
ib. Defective Maternal Ubiquitin in Angelman’s Syndrome
- accumulation of undegraded protein → neuronal damage
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ii. Prader-Willi Syndrome
- 4 megabase deletion on paternal chromosome 15q
- 1 of 10,000 live births
- manifestations
- affects males and females
- moderate mental and developmental retardation
- neonatal hypotonia and failure to thrive
- very low recurrence risk
- aggressive/psychotic behavior
- short stature, with small hands, feet
- poor feeding in neonatal period
- hypogonadism, underdeveloped genitalia
- hyperphagia and obesity by ages 2-4 years
- distinctive facial features
- eating disorder
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iii. Angelman Syndrome
- 4 megabase deletion on maternal chromosome 15q
- manifestations
- severe mental retardation
- seizures
- ataxic gait
- behavior disorders
- inappropriate/unprovoked laughter/happy disposition (aka happy
puppet syndrome)
- jerky, flexed, uncoordinated movements
- microcephaly
- lack or minimal speech
- sleep disturbance
- affects males and females
- puppet-like posture of limbs
- very low recurrence risk
- hypotonia
- severe developmental delay
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11. Uniparental Disomy
- rare
- both copies of chromosome are contributed by one parent (may cause problems if the
chromosome contains an imprinted region or a mutation)
- 25-30% of Prader-Willi cases are caused by maternal uniparental disomy of chromosome
15
- smaller percentage of Angelman syndrome caused by paternal uniparental disomy of
chromosome 15
12. Factors Responsible for Variable Expression of Disease
- most genetic diseases vary in the degree of phenotypic expression
- some may be severely affected
- others are more mildly affected
a. Environmental Influences
- autosomal recessive disease xeroderma pigmentosum expressed more severely in
those who are exposed more frequently to ultraviolet radiation
b. Allelic Heterogeneity
- missense mutations in factor VIII gene tend to produce less severe hemophilia than
nonsense mutations
c. Heteroplasmy
- in mitochondrial pedigrees
d. Modifier Loci
- disease expression may be affected by the action of other loci
13. Pleiotropy
- single disease-causing mutation affects multiple organ systems
- common amongst genetic diseases
- examples
- Marfan syndrome
- cystic fibrosis
14. Locus Heterogeneity
- the same disease phenotype can be caused by mutations at different loci
- often involves mutations in coding of multi-chain molecules
- ex: osteogenesis imperfecta
- brittle bone disease
- mutations in collagen genes
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15. Anticipation
- most recent generations develop disease at earlier age or greater severity
- gradual expansion of trinucleotide repeat polymorphisms within or near a coding gene
- individual with few repeats is mildly or non-affected
- increased numbers of repeats transmitted over generations causes increasing severity or
earlier onset
- ex: myotonic dystrophy
Fragile X syndrome
Huntington disease
D. Somatic Cell Gene Defects
- mutations are not inherited except by the cells in the lineage of the mutated cell
- important in tumorigenesis

GENE TESTING
A. Genetic Tests
- direct examination of the DNA molecule
- biochemical tests for the gene products
- chromosomal analysis
B. Reasons for Genetic Testing
- carrier screening
- identifying unaffected individuals who carry one copy of a gene for a disease that requires two
copies in order for the disease to be expressed
- preimplantation genetic diagnosis (screening embryos for disease)
- prenatal diagnostic testing
- newborn screening
- presymptomatic testing
- predicting adult-onset disorders such as Huntington’s disease
- estimating the risk of developing adult-onset cancers and Alzheimer’s disease
- confirmational diagnosis of a symptomatic individual
- forensic/identity testing
C. DNA Probes
- sequences are complementary to the mutated sequences
1. Uses - examine an individual’s genome
- make comparisons of the sequence of DNA bases in one of their genes with a normal version of
that gene
D. Some Examples of Diseases Detected by Genetic Testing
- alpha-1-antitrypsin deficiency (emphysema and liver disease)
- amyotrophic lateral sclerosis (Lou Gehrig’s disease, progressive motor function loss)
- Alzheimer’s disease (APOE, late-onset variety of senile dementia)
- Gaucher’s disease (enlarged liver and spleen, bone degeneration)
- inherited breast and ovarian cancer (BRCA 1 and 2, early-onset tumours)
- congenital adrenal hyperplasia (hormone deficiency, ambiguous genitalia)
- cystic fibrosis (disease of lung and pancreas)
- Duchenne muscular dystrophy/Becker muscular dystrophy (severe to mild muscle wasting,
deterioration, weakness)
- dystonia (muscle rigidity, repetitive twisting movements)
- factor V-Leiden (blood-clotting disorder)
- fragile X syndrome (leading cause of inherited mental retardation)
- galactosemia (metabolic disorder affects ability to metabolise galactose)
- haemophilia A and B (bleeding disorders)
- hereditary hemochromatosis (excess iron storage disorder)
- Huntington’s disease (progressive, lethal, degenerative neurological disease)
- Marfan syndrome (connective tissue disorder)
- mucopolysaccharidosis (deficiency of enzymes in breaking down glycosaminoglycans)
- myotonic dystrophy (progressive muscle weakness, adult muscular dystrophy)
- phenylketonuria (missing enzyme, phenylalanine hydroxylase, correctable by diet)
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- sickle cell disease (blood-cell disorder)
- spinal muscular atrophy (severe, usually lethal, progressive muscle-wasting disorder)
- Tay-Sachs disease (fatal neurological disease of early childhood)
- thalassemias (anemias)
E. Advantages and Disadvantages of Gene Testing
1. Advantages
- clarify a diagnosis
- allow families to avoid having children with devastating diseases
- identify people at high risk for conditions that may be preventable
2. Disadvantages
- gene tests are targeted to healthy, presymptomatic individuals who are identified as being at high
risk because of a strong family medical history for the disorder
- give only a probability for developing the disorder
- difficulty in interpreting a positive result because some people who carry a disease-associated
mutation may never develop the disease
- implications for family members since genetic information is shared
- uncertainties surrounding test interpretation
- current lack of available medical options for some diseases
- potential for provoking anxiety
- risks for discrimination and social stigmatisation