GENETIC BASIS OF DISEASES

DR. YUSUF M. ABDULLAHI (MBBS, FMCPath)

DEPARTMENT OF HISTOPATHOLOGY
COLLEGE OF MEDICAL SCIENCES,
GOMBE STATE UNIVERSITY/UNIMAID
 INTRODUCTION
• Genes and the environment play paramount role in
the causation of disease.
• With advancing knowledge, it is becoming more and
more apparent that most diseases including cancer
have genetic bases.
• Permanent alteration of a DNA (mutation) is
responsible for several disease states eg cancers,
susceptibility to certain infections, congenital
anormalies etc.

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 INTRODUCTION
• Genetics is a branch of science that deals with
the study of genes, genetic variations, and
heredity in living organism
 INTRODUCTION
• Gene is the biological unit of heredity

• Gene hold the information to build and

maintain their cells and pass genetic traits to
offsprings

• In cells, a gene is portion of

DNA
INTRODUCTION
Gene (DNA)

RNA formation

Protein formation

Cell structure Cell enzymes

Cell function
 INTRODUCTION
• Congenital Disease
Diseases which are present at birth.
• Hereditary/Familial Disease
Diseases which are derived from one’s parents
and transmitted in the gametes through the
generations
NOTE : Not all congenital diseases are genetic (congenital
Syphilis) and not all genetic diseases are congenital
(Huntington disease)

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 MUTATIONS
Definition:
• Permanent changes in the DNA.
• Those that affect germ cells are transmitted to
the progeny.
• Mutations in the somatic cells are not
transferred to the progeny but are important in
the causation of cancer and some congenital
diseases.
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 CAUSES OF MUTATIONS
• Chemicals
 Nitrous acid
 Alkylating agents
 5- bromouracil
 Antiviral drug iododeoxy uridine
 Benzpyrene in tobacco smoke
• X – rays & ultraviolet light
• Certain viruses and bacteria
 TYPES OF MUTATIONS
• Based on the extent of genetic change, mutations may
be classified into
• Genomic mutations- loss or gain of whole
chromosomes giving rise to monosomy or trisomy.
• Chromosomal mutations- rearrangement of genetic
material causing visible structural changes in the
chromosome.
• Gene mutation- submicroscopic mutations causing
partial or complete deletion of a gene or more often
affect a single base pair
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CLASSIFICATION OF GENETIC DISEASES:

• Single Gene Defects/Mendelian Disorders.

• Disorders with Multifactorial or Polygenic

inheritance.

• Cytogenetic Disorders.

• Disorders showing atypical patterns of

inheritance.
 Mendelian
Disorders
A genetic disease caused by a single
mutation in the structure of DNA,
which causes a single basic defect with
pathologic consequences
 MENDELIAN DISORDERS
• These are as a result of expressed
mutations in single genes of large effect.
• Transmission can be by:
– Autosomal dominant pattern
– Autosomal recessive pattern
– Sex linked pattern

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 Autosomal Dominant Disorders
• Manifested in the heterozygote state
• Affects both sexes and is transmitted by both
• If one of a couple is affected, each child has 50%
chance of been affected
• Occasionally can arise denovo in a patient without
inherited gene disorder
• Clinical features are modified by reduced penetrance
and variable expressivity

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 Autosomal Dominant Disorders
• Usually delayed onset (adulthood).
• Most mutations lead to decreased production
of a gene product or inactivated product.
• A few mutations lead to gain of function

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Inheritance Pattern:
• Typical
mating pattern is a
heterozygous affected
individual with a
homozygous unaffected
individual.

•Every child has one chance in

two of having the disease

• Both sexes are affected

equally..
Examples of Autosomal Dominant Disorders

• Nervous system- Neurofibromatosis,

Huntington disease
• Urogenital system- Adult polycystic kidney
disease
• GIT- Familial adenomatous polyposis coli
• Haematology- Hereditary spherocytosis, von
willebrand disease
• Skeletal- Marfan syndrome, Ehlers-Danlos
syndrome, Achondroplasia
• Metabolic- Familial hypercholesterolaemia
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NEUROFIBROMATOSIS

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ADULT POYCYSTIC KIDNEY DISEASE

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FAMILIAL ADENOMATOUS POLYPOSIS COLI

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 Autosomal Recessive Disorders
• Largest group of Mendelian Disorders
• Manifests only in the homozygote state
• Trait does not usually affect the parents
• Offspring each have 25% chance of been
affected
• Expression of the defect tend to be more
uniform than autosomal dominant
• Complete penetrance is common

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 Autosomal Recessive Disorders
• Onset is frequently early in life
• New mutations are rarely responsible for
clinical manifestations
• Enzyme proteins are usually affected by loss
of function
• Many inborn errors of metabolism are
autosomal recessive disorders

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Inheritance Pattern:
 Typical mating pattern is two
heterozygous unaffected (carrier)
individuals.

 The trait does not usually affect the

parent, but siblings may show the
disease

 Siblings have one chance in four of

being affected

 Both sexes affected equally.

Examples of Autosomal Recessive Disorders

• Haematologic- Sickle cell anaemia,

Thalassemias
• Urinary system- Infantile polycystic kidney
disease
• Metabolic- Cystic fibrosis, Galactosemia,
Phenylketonuria.
• Endocrine- Congenital adrenal hyperplasia
• Nervous- Neurogenic muscular atrophies

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 X-Linked Disorders
• All sex-linked disorders are X-linked, and almost all
are recessive
• Accounts for a small number of well-defined clinical
conditions
• Affected males transmits only to daughters (carriers)
and not his sons
• Heterozygous females do not express the full
phenotypic change
• Usually expressed only in males.
• Rarely, due to random X-inactivation, a female will
express disease, called manifesting heterozygotes.
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Inheritance
Pattern:
• Disease usually passed on
from
carrier mother.

• Expressed in male offspring,

females are carriers.

• Skipped generations are

commonly
seen.

• In this case, Recurrence risk is

half of sons affected, half of

the daughters are carriers.
Recurrence risk:
All the daughters
are heterozygous
carriers and all the
sons are
homozygous
normal.
 Examples of X-linked disorders
• Haematologic- G-6-PD deficiency,
Haemophilia A and B
• Musculoskeletal- Duchenne muscular
dystrophy
• Metabolic- Diabetes insipidus, Lesch-nyhan
syndrome
• Nervous- Fragile X syndrome
• Immune- Wiskott-aldrich syndrome

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Biochemical and molecular basis
of Mendelian Disorders
1. Enzyme defects and there consequences
2. Defects in membrane receptor and transport
system
3. Alteration in structure, function or quantity of
nonenzymic proteins
4. Mutations resulting in unusual reaction to
drugs

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 DISORDERS WITH MULTIFACTORIAL
INHERITANCE
• Multifactorial disorders result from the
combined action of environmental influences
and two or more mutant genes having addictive
effect.
• Involved in many physiologic characteristics of
humans e.g. height, weight, hair color
• The disorder becomes manifested only when a
certain number of effector genes, as well as
conditioning environmental influences are
involved 29
Examples of multifactorial disorders
• Cleft lip/palate
• Congenital heart disease
• Coronary heart disease
• Hypertension
• Gout
• Diabetes mellitus
• Pyloric stenosis
• Skeletal Abnormalities
• Neural Tube Defect
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CLEFT LIP/PALATE

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CONGENITAL HEART DISEASE

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NEURAL TUBE DEFECTS

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Cytogenetic
Disorders
 CYTOGENETIC DISORDERS
• The normal chromosome count is expressed as 46XX
in the female and 46XY in the male
• An exact multiple of the HAPLOID number is called
EUPLOID
• If an error occurs in meiosis or mitosis and a cell
acquires a chromosome complement not an exact
multiple of 23, it is referred to as ANEUPLOIDY

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 KARYOTYPING
• Basic tool of cytogeneticist
• Karyotype is a photographic representation in
which chromosomes are arranged in order of
decreasing length
• Giemsa stain (G banding) technique — each
chromosome can be seen to possess a
distinctive pattern of alternating light and dark
bands of variable widths

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 CYTOGENETIC DISORDER

• Cytogenetic disorders may result from

structural or numeric abnormalities of
chromosomes

• It may affect autosomes or sex chromosomes

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 Structural Abnormalities
• Usually result from chromosomal breakage,
resulting in loss or rearrangement of genetic
material.
• Patterns of breakage:
– Translocation
– Isochromosomes
– Deletion
– Inversions
– Ring Chromosomes
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General Features of Cytogenetic Disorders
• Associated with absence, excess, or abnormal
rearrangements of chromosomes.

• Loss of genetic material produces more severe

defects than does gain.

• Abnormalities of sex chromosomes generally

tolerated better than those of autosomes

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General Features of Cytogenetic Disorders

• Sex chromosomal abnormalities are usually

subtle and are not detected at birth.

• Most cases are due to de novo changes

(i.e. parents are normal and recurrence in
siblings is low).

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Cytogenetic Disorders
involving Autosomes
Trisomy 21/Down’s Syndrome
• Most common chromosomal disorder

• Down syndrome is a chromosomal

abnormality characterized by the presence
of an extra copy of genetic material on the
21st chromosome

• Trisomy 21 is caused by a meiotic

nondisjunction event.
 Trisomy 21/Down’s Syndrome
• With nondisjunction, a gamete (i.e., a sperm or
egg cell) is produced with an extra copy of
chromosome 21; the gamete thus has 24
chromosomes
• When combined with a normal gamete from the
other parent, the embyo now has 47 chromosomes,
with three copies of chromosome 21.
• Maternal age has a strong influence

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TRISOMY-21 KARYOTYPE
 Down Syndrome Features
Flat facial profile and
oblique palpebral fissures Thickened epicanthic fold

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Single simian crease – Trisomy 21

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Other Trisomy Syndromes:

• Trisomy 18 : Edwards Syndrome.

• Trisomy 13 : Patau Syndrome.

Trisomy 13 Patau syndrome

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Prominent bilateral cleft lips in Trisomy 13

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Polydactyly in Trisomy 13

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Cyclopia with proboscis in Trisomy 13

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Trisomy 18 Edwards syndrome

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Micrognathia with small chest (Edward syndrome)

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Overlapping fingers suggestive of
Edward syndrome

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TRISOMIES FEATURES

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 Cytogenetic disorders involving
sex chromosomes
• They induce subtle chronic problems relating
to sexual development and fertility
• They are often difficult to diagnose at birth
and many are 1st recognised at puberty
• The higher the number of X chromosome in
either male or female, the greater the
likelihood of mental retardation

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 Examples
• Klinefelter Syndrome

• Turner Syndrome

• XYY Syndrome

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 Klinefelter’s Syndrome
(Seminiferous tubule dysgenesis)
• Defined as Male Hypogonadism,
develops when there are at least two X
chromosomes and one or more Y
chromosomes.

• Usual karyotype is 47,XXY. The extra X

may be maternal or paternal.
 Klinefelter’s Syndrome

• Results from nondisjunction of sex

chromosome during meiosis.

• Risk factors include advanced maternal

age and a history of exposure to radiation
in either parent.
Klinefelter Syndrome XXY
Karyotype

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 Klinefelter’s Syndrome
• Increase in body length between soles and
pubis.
• Reduced facial, body and pubic hair.
• Gynecomastia.
• Testicular atrophy.
• Infertility.
• Mild mental retardation

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Turner’s Syndrome (Ovarian dysgenesis)
• Primary hypogonadism in phenotypic females.
• Results from partial or complete monosomy of
the X chromosome.
• Most common cause is absence of one X
chromosome.
• Less commonly, mosaicism, or deletions on
the short arm of the X chromosome.

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Turner’s syndrome XO
karyotype

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 Uterus with streaks of vestigial ovarian
tissue in a 55yr old woman with Turners
syndrome

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 Genetics and cancer
• Cancer is a genetic disease
• Gene mutations involved in cancer formation
include
(a) Oncogenes
(b) Cancer suppressor genes
(c) Genes that regulate apoptosis
(d) Genes that regulate DNA repair
(e) Metastasis genes

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 Molecular biology in disease
diagnosis
• Diagnosis of genetic diseases require
examination of genetic material
hence cytogenetic and molecular
analysis play important roles.
• Prenatal chromosomal analyses
• Postnatal chromosomal analyses

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PRENATAL GENETIC ANALYSIS
• Should be offered to all patients who are at
risk of having cytogenetically abnormal
progeny.
• It can be performed on cells obtained by
– Amniocentesis,
– On chorionic villus biopsy material,
– On umbilical cord blood

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 INDICATIONS FOR PRENATAL GENETIC
ANALYSIS
• A mother of advanced age (>35 years) because
of greater risk of trisomies
• A parent who is a carrier of a cytogenetic
disease
• A parent with a previous child with a
chromosomal abnormality
• A fetus with ultrasound-detected abnormalities
• A parent who is a carrier of an X-linked
genetic disorder (to determine fetal sex)
• Abnormal levels of AFP, βHCG, and estriol 74
 POSTNATAL GENETIC ANALYSIS
• Postnatal genetic analysis is usually performed on
peripheral blood lymphocytes.
• Indications are as follows:
– Multiple congenital anomalies
– Unexplained mental retardation and/or developmental delay
– Suspected aneuploidy (e.g., features of Down syndrome)
– Suspected unbalanced autosome (e.g., Prader-Willi syndrome)
– Suspected sex chromosomal abnormality (e.g., Turner syndrome)
– Suspected fragile-X syndrome
– Infertility (to rule out sex chromosomal abnormality)
– Multiple spontaneous abortions (to rule out the parents as carriers
of balanced translocation; both partners should be evaluated) 75
 Direct Gene Diagnosis
• The diagnostic methods of the human
genome available include;
(a) Polymerase Chain Reaction (PCR)
(b) Flow Cytometry
(c) Florescent In Situ Hybridization (FISH)
(d) Filter Hybridization

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Florescent In Situ Hybridization technique
(FISH) for chromosomal analysis

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THANK YOU FOR LISTENING

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