Gene defects

Dr. Mehzabin Ahmed

 Development
Ova Sperm
Zygote
Embryo
Fetus
Neonate
Infant
Toddler
Teenager
Adult
Old age
 Patterns of embryological maldevelopment
• Malformations: Intrinsic abnormalities occurring during the development
process. These may involve single or multiple organ systems. E.g.-
congenital heart diseases, neural tube defects
• Deformations: These abnormalities arise later in the fetal life and are due to
mechanical factors. These result in changes in shape, form and position of the
body. E.g. Clubfeet. These may be due to
a) Maternal factors like small uterus, bicornuate uterus, and leiomyomas.
b) Fetal factors like multiple fetuses, abnormal presentation, oligohydramnios
• Disruptions: There is a secondary destruction or interference in
development of an organ or a body region, that was previously normal. These
are not heritable. E.g. Amniotic bands formed following rupture of amnion
during fetal development.
 Patterns of embryological maldevelopment

• Agenesis- complete failure of organ development.e.g., renal agenesis

• Hypoplasia- incomplete organ development. e.g.,phocomelia
(thalidomide administration), microcephaly ( alcohol consumption)
• Dysraphism- failure of embryological fusion.e.g., meningomyelocele
• Atresia- failure of lumen formation in hollow organs.e.g., esophageal
atresia, biliary atresia
• Ectopia- abnormal location of an organ or tissue.e.g., maldescent of
the testes
The nucleus of every human cell contains a vast chemical
information database, that carries all the instructions the cell needs
to do its job. This database is DNA. DNA exists as two long,
intertwined, thread-like strands packaged in units called
chromosomes. Each cell has 46 chromosomes in 23 pairs. DNA is
made up of four chemicals, or bases, arranged in various sequence
patterns. A group of 3 such pairs is called a codon and many such
codons arranged in specific sequences forms a gene. Each codon
codes for a specific amino acid and the whole gene therefore codes
for specific proteins, structural or functional. Even slight alterations
in a gene can produce an abnormal protein, which, in turn, can lead
to cell malfunction, and eventually, to disease. Such alterations are
called mutation. Other more common (or frequent) changes in a
gene's DNA don't automatically cause disease, but they can
increase the chances that a person will develop a particular disease
is called a genetic risk factor.
 Causes of congenital malformations
Genetic causes:

b) Single gene mutations: These account for a small percentage of birth

defects. Mutations are changes in the gene structure and can be of
different types, for eg. deletions, point mutations,

c) Chromosomal aberrations (abnormalities) These arise usually due to

defective gametogenesis and are therefore not familial. However some
chromosomal abnormalities like some forms of Down's syndrome are
transmissible and can be passed on from parent to child.
 Causes of congenital malformations
Teratogens
• Drugs & chemicals, e.g. Thalidomide, Alcohol
• Ionizing radiation, e.g. X-rays
• Maternal infections, e.g. maternal infection by TORCHS - Toxoplasmosis,
Rubella, Cytomegalovirus, Herpes virus, Syphilis
• Maternal diseases, e.g., diabetes, phenylketonuria, endocrine disorders
Multifactorial genetic disorders:
• These are disorders where many gene loci are involved or defective and
environmental factors also play an important role in their development, e.g.-
neural tube defects, club feet, cleft lip & palate
 Teratogens
• The embryological development in the first 3mths (1st trimester) is the most
crucial period, as most of the organogenesis (organ formation) takes place in
this period

• Exposure to teratogens (agents that cause developmental malformation, like

drugs or viruses) in this period induces abnormal fetal development.

• Development of malformation depends on dose & duration of exposure, time

of exposure, & individual susceptibility to the agent
 Effect of Developmental disorders

Failure of normal embryological development may result in:

• Death soon after fertilization- if the error is very large

• Death of the fetus late in the pregnancy or shortly after birth- e.g.,

bilateral renal dysplasia

• Severe illness/ disease but not lethal- e.g., Fallot’s tetrology

• Mild disease with normal existence-e.g., small atrial or ventricular

septal defect
 Definition - Mutations

Permanent changes in the base pairs of a DNA molecule

Germ cell mutations Somatic cell mutations

Inherited Diseases Cancers

Congenital malformations
 Single gene mutations - (Mendelian disorders)

• Mutations occur spontaneously during the process of DNA

replication
• Certain environmental factors increase the rate of so called
spontaneous mutations e.g.
• Radiations,
• Chemicals,
• Viruses

• Single gene mutation disorders may be classified on the basis of

pattern of inheritance:
• AD/AR/X-linked R/D
 Mutations may be classified into three categories:

• Genome mutations involve

– loss or gain of a whole chromosome (Monosomy, Trisomy) or
– result from structural changes in the chromosome with
rearrangement of the genetic material (Translocations,
Deletions)
• Gene mutations affect a partial or complete deletion of a gene or
more often a single base
 Significance of mutations

Mutations can interfere with protein synthesis at various levels

• Transcription may be suppressed with gene deletions or point
mutations involving promoter sequences with decreased synthesis
of a protein
• Abnormal mRNA processing may result from mutations affecting
introns or splice junctions or both decreased synthesis of protein
• Translation is affected if a stop codon (chain termination) is created
within an exon and no protein is synthesized
• Some point mutations may lead to the formation of an abnormal
protein without impairing any step in protein synthesis
 Pathogenesis of Single – Gene (Mendelian ) disorders
(Biochemical and molecular mechanisms)

• Alterations involving single genes may lead to the formation of an abnormal

protein or reduction in the output of the protein
• Mutations may affect different stages in protein synthesis
• Phenotypic (clinical ) effects of mutation may result directly or indirectly from
abnormalities in protein synthesis
• Mechanisms of single gene disorders may be classified into four categories:
5. Defects in enzyme proteins and their functions, eg: lysosomal storage disorders
6. Defects in membrane receptors and transport proteins, eg: cystic fibrosis,
achondroplasia
7. Alteration in structure, function or quantity of non-enzyme proteins, eg: Marfan
syndrome, osteogenesis imperfecta
8. Mutations resulting in unusual reaction to drugs, eg: glucose 6phosphate
dehydrogenase deficiency (hemolysis of RBCs when the patient takes antimalarial
drugs)
 Inheritance patterns of single gene disorders

These follow the Classical Mendelian patterns of inheritance

• Autosomal dominant- the affected gene produces disease in a
heterozygote as well as a homozygote. It can affect both male &
female and offsprings of affected individuals are also affected, thus
all generations are affected
• Autosomal recessive- the gene produces disease only in the
homozygote. The heterozygote are carriers of the disease. Both
males & females are affected and disease is not seen in all
generations
• X-linked pattern- the abnormal gene is on the X chromosome,
the males manifest the disease in the heterozygote state and
the heterozygote females are the carriers
Non classical inheritance
Mitochondrial inheritance - the mitochondrial DNA (that codes for
mitochondrial proteins) transmits the disease due to a defect in its
sequences.
• This DNA is contributed by the oocyte and so it is transmitted by
the affected female, affected male cannot transmit the disease to his
children
 Achondroplasia

• It is the most common disease of the growth plate, resulting in

dwarfism.
• In the normal growth plate, activation of a receptor FGFR3 causes
cartilage proliferation to stop.
• In achondroplasia these receptors are in a state of constant activation
thus the cartilage does not proliferate and the patient remains short.
• It is an autosomal dominant disorder. There is a point mutation of the
gene coding for FGFR3.
• There is no change in longevity, intelligence or reproductive status.
 Short proximal
extremities, relatively
normal length of trunk,
An enlarged head
with a bulging forehead
Conspicuous
depression of the nose
 Marfan’s Syndrome

• It is the disorder of the connective tissue resulting in changes in

the skeleton, eyes, and CVS.
• It is mostly familial - 75% and is transmitted by autosomal
dominant inheritance. The remaining are sporadic and result from
new mutations.
• Extracellular matrix contains microfibrils, made up of fibrillin.
These microfibrils form a scaffold in of 2 types and is coded by 2
separate genes FBN 1 and FBN 2. Mutations of FBN 1 cause
Marfan’s syndrome. Tissues rich in microfibrils: aorta, ligaments,
and ciliary zonules of the lens.
 Lax, hyperextensible Ectopia lentis-
joints-esp. thumb
dislocated lens

Longheaded, frontal Chest: Pectus

bossing, prominent excavatum or
supra orbital ridges. pigeon breast

Weak walls of the aorta can cause tears or

dissections and fatal hemorrhages can occur.
Heart- mitral valve prolapse & aortic regurgitation
 Skeleton: Tall, long
limbs, long fingers
and toes. Ratio of
upper segment to
lower segment is
lower than normal.

Kyphoscoliosis
 Multifactorial disorders

Neural Tube Defects

These are the most common CNS malformations. There is a
failure of a portion of the neural tube to close or its
reopening, causing abnormalities involving both neural
tissue and overlying bone and soft tissues.
Folate deficiency in the initial weeks of gestation is a risk
factor.
The defects can be:
1) Anencephaly: It is a malformation involving the anterior end of the
neural tube. There is absence of brain and calvaria. Malformation
involves the forebrain in particular and posterior fossa structures are
often spared.
2) Encephalocele: A diverticulum of malformed CNS tissue extends
through a defect in the cranium. It occurs most often in the occipital
region or the posterior fossa.
3) Spinal dysraphism or spina bifida: Failure of closure or reopening of
caudal portions of the neural tube. It involves the spinal cord. It may
be an asymptomatic bony defect or a severe malformation with an
outpouching of a segment of spinal cord with the overlying meanings.
• Meningomyelocele: Protrusion of CNS tissue through a defect in
vertebral column.
• Meningocele: Protrusion of meanings.
 Clinical features
Due to structural abnormalities of the cord and superimposed infections
of the skin overlying the lesion.
 Meningomyelocele occur most commonly in the lumbosacral region.
 The patient presents with motor and sensory dysfunction in lower
limbs and disturbances in bowel and bladder control.

Antenatal diagnosis:
1) Elevation of α- fetoproteins in maternal blood
2) Imaging methods
 Club foot

Cleft lip & Palate