Introduction to Medical

Genetics
By/ Rasha Saifaldein Teleb
 What’s Medical Genetics?

“Genetics – study of individual genes and their

effects”:
Includes studies of inheritance, mapping disease,
diagnosis, treatment, and genetic counseling
 Genetics – history and key concepts…
1860s Mendel’s 1910 Thomas
work on peas Morgan’s work 1953 James Watson
allows the on fruitflies and Francis Crick
conclusion that demonstrates publish the double helix
traits are inherited that genes lie on model for DNA’s
through discrete chromosomes chemical structure
units passed from
one generation to
the next
1958 Crick proposes
1940s Barbara the ‘central dogma’ for
McClintock biological information
1870s Friedrich describes flow: that DNA makes
Miescher describes mobile genetic RNA makes protein
nucleic acids elements in
maize
2001 initial results
from the Human
1951 Rosalind Genome Project
1909 The word ‘gene’ Franklin shows published
coined by Danish botanist pictures of DNA
Wilhelm Johannsen using accurate X-
ray diffraction
patterns.
 Genetic Information
 Gene – a segment of DNA molecule
(base sequence) that codes for the
synthesis of a single polypeptide that is
translated into a certain character or
function.

 Genome – the collection of

genetic information.

 Chromosomes – storage units of

genes.
 Locus – location of a gene/marker
on the chromosome.

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 Genetic Information
• In human, normal somatic cells contain 46 chromosomes (diploid number,
2n):
- 44 are termed autosomes
- two are sex chromosomes (XX) or (XY).
So Normal Karyotype is 44, XX or 44, XY.
• Chromosomes are paired (23 pairs of homologous chromosomes). In each
pair, one homolog is maternal and the other is paternal in origin.
• Gametes (eggs and sperms) contain 23 chromosomes (haploid number, n).
• Allele – one variant form of a gene/marker
at a particular locus.

• Each gene is formed of 2 alleles, located at

the same locus on each homologue (paternal
and maternal) of a specific chromosome

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 Glossary & Definitions
• Phenotype - the physical description of the
character in an individual organism
– i.e a green eyes
• Genotype - the genetic constitution of the organism
• Mutation - a change in the genetic material,
usually rare and pathological
 Some Facts
• In human beings, 99.9% bases are same

• Remaining 0.1% makes a person unique (Different

characteristics, how a person looks, diseases he or she
develops)
•
• Genes can regulate other genes by turning them on or
off, specify the exact structure of proteins, which then
control the activities of the cells and specify RNA,
which is required for protein synthesis.
 Cell
Division
Immunofluorescence
Study-Phases of cell
division
Genetic Diseases
Genetic Diseases

Unifactorial Chromosomal Multifactorial

AD Numerical

AR Structural

X-linked Microdeletions

Mitochondrial
The contributions of genetic and environmental
factors to human diseases
Haemophilia Peptic ulcer
Osteogenesis imperfecta Diabetes
Duchenne Club foot
muscular dystrophy Pyloric stenosis Tuberculosis
Dislocation of hip

GENETIC ENVIRONMENTAL

Spina bifida Scurvy

Phenylketonuria Ischaemic heart disease
Galactosaemia Ankylosing spondylitis

Rare Common
Genetics simple Genetics complex
Unifactorial Multifactorial
High recurrence rate Low recurrence rate
Numerical CHROMOSOMAL
ANOMALIES
 Numerical Chromosomal
Abnormalities
• Changes in the number of chromosomes:
– Polyploidy
• Somatic cells contain multiples of haploid
number of chromosomes
• 3n, 4n, 5n etc.
– Aneuploidy (Heteroploidy)
• Deviation from the diploid number of
chromosomes
• 2n + 1, 2n -1 etc.
 Mechanism of Aneuploidy
1- Non-dysjunction: failure of separation of
chromosomes during cell division.
• Formation of 2 types of gametes (both abnormal)
• Fusion of either of these abnormal gametes with a
normal gamete can result in trisomy or monosomy
• May involve autosomes or sex chromosomes
 In meiotic nondisjunction
- This product of fertilization with normal gamete would be
monosomic and trisomic offspring (Aneuploidy)
 MOSAICISM
• The presence of more than one
genetically distinct cell line in the
body

• A mosaic individual is made of 2

(or more) cell populations, coming
from only 1 zygote

• Numerical mosaic anomaly is

usually due to a mitotic non-
disjunction
 Karyotypes
• Numerical chromosomal
anomalies are diagnosed by
Karyotype.

• It is a photograph of one’s
chromosomes, grouped in
pairs of homologous
chromosomes by size.
 Analyzing Karyotypes:
1. Are there 46 chromosomes?
2. Are there 2 identical chromosomes in each pair of
autosomes and 2 sex chromosomes?
3. Are there any rearrangements between chromosomes
or large, obvious deletions?
 Karyotypes DO NOT show:

1. Individual DNA strands or genes or the DNA

sequence
2. The number of genes in a chromosome
3. The presence of gene mutations
 7 Chromosome Disorders caused
by Nondisjunction

1. Down syndrome (trisomy 21)

2. Edwards syndrome (trisomy 18)
3. Patau syndrome (trisomy 13)
4. Klinefelters syndrome (trisomy XXY)
5. XYY syndrome (trisomy XYY)
6. XXX syndrome (trisomy X)
7. Turners syndrome (monosomy XO)
**Nearly all other nondisjunctions lead to death of
embryo or child before adulthood!
STRUCTURAL CHROMOSOMAL
ANOMALIES
• Deletion: Loss of a segment from a chromosome
which may result in the loss of important genetic
material (un-balanced rearrangements).
• Inversion: Occurs when a segment of chromosome
breaks, and rejoining within the chromosome
effectively (balanced rearrangements).
• Translocation: is the detachment of a chromosome
segment from its normal location and its attachment
to another chromosome.
 Reciprocal translocation
• The cell contains two complete copies of all
chromosomal material although in different order
e.g. part of the short arm of the chromosome (4)
takes place with part of chromosome (10).
• When there is exchange of segments with no
associated loss of genetic materials, this is termed
balanced translocation.
• Reciprocal translocation between chromosome 22
and the long arm of chromosome 9 (the
Philadelphia chromosome), occurrence of this
translocation in hematopoietic cells can produce
chronic myelogenous leukemia (CML)
 Robertsonian translocation
• Short arms of two non homologous
chromosomes are lost and the long arms
fuse at the centromere to form a single
chromosome
• Confined to the acrocentric chromosomes
(13, 14, 15, 21, and 22)
• Although carriers have only 45
chromosomes in each cell, they are
phenotypically unaffected (balanced
translocation carrier)
• When a carrier produces offsprings there is
a risk of producing an unbalanced
karyotype (Down syndrome). The patient
has one 14 chromosome, two 21
chromosomes and fused 14,12 chromosome
giving a total of 46 chromosomes ( trisomy
21).
Single Gene Mutation Disorders
(Modes of Inheritance)
 Autosomal
Dominant
Inheritance

• One muted allele is enough to express the character

• Each affected individual has one affected parent
• Males and females may be affected
• Pattern of inheritance is vertical (passed from generation to generation)
• 50% risk to children
• Example: spherocytosis, achondroplasia.
Autosomal
Recessive
Inheritance
• The two gene alleles should be mutated to express the character
• Do not need a parent who is affected; each parent must be a carrier of
the recessive gene
• Males and females may be affected
• Pattern of inheritance is horizontal (usually seen in siblings)
• Offspring of parent with the condition are obligate carriers
• 25% risk to children
• Example: thalassemia.
 Sex - linked
recessive
inheritance
• Gene is located on X chromosome
• Female is usually clinically normal and disorders are typically seen more often in
males than females
• Absence of male-to-male transmission
• Risk for inheriting an X-linked condition:
- 100% for daughters of affected fathers to be carriers
- 0% for sons of affected fathers to be affected
- 50% for daughters of carrier or affected mothers to be carriers
- 100% for sons of affected mothers to be affected
-50% for sons of carrier mothers to be affected

• Example: hemophilia and G6PD.

Down Syndrome
(Trisomy 21)
• Is a genetic disorder caused by the presence of all, or
part of a third copy of chromosome 21.
• First described by physician, “John Langdon Down” in
18th century.
• Karyotype:
47,XX,+21 (female) or
47,XY,+21 (male)
• Incidence: Incidence in the general population is 1/600
- 1/800 births
 Genetic types of DS
1-Nondisjunction (Trisomy 21) : 95%
failure of separation of chromosome 21 .. So, zygote contain
3 of 21.
2-Translocation of chromosome 21: 4%
Breaking and attaching to other chromosomes (14, 21)
during cell division. Patient has 46 chromosomes but
functionally is trisomic for 21.
May be inherited or De-Novo
3-Mosaicism: 1%
non disjunction after zygote formation.
Results in two cell lines ( normal cells and trisomic cells)
 Risk factors
• Advancing maternal age – usually women of age 35
and above

• Trisomic mothers.

• Parents who are carriers of the genetic translocation

for Down syndrome
 Clinical Features
General
•Mental retardation
•Hypotonia
•Delayed developmental
milestones
•Weight, length and HC are
less in DS
•Reduced growth rate
Cranio-facies
• Fine silky hair
• Mild microcephaly
• Flat occiput.
• Small dysplastic ears
• Upward slanting palpebral fissures.
• Epicanthic folds.
• Speckled irides (Brushfield spots)
• Small nose, flat nasal bridge
• Protruding tongue, open mouth
• High-arched palate
Hands and feet
• Simian crease
• Short, broad hands
• Hypoplasia of middle phalanx of 5th finger
• Gap between 1st and 2nd toes
 Diagnosis
• Karyotyping
 Other Health-related problems
(complications)
– Cardiovascular problems 50% of DS
AVSD, VSD, ASD and PDA
– Endocrine problems
thyroid problems , diabetes mellitus
– Gastrointestinal problems 5%
•duodenal, esophageal and anal atresia
• Hirschprung‟s disease
•celiac disease.
– Hematological problems
• Acute leukemia
•transient myeloproliferative disease
– Neurological problems
•Epilepsy
•severe behavioral problems
•Alzheimer’s disease
•memory problems
•autism.
– Sleep problems
•Sleep apnea, other sleep disturbance

– Visual problems
• Refractive disorder, squint, nystagmus, and cataract

– Hearing problems
• Hearing loss, conductive hearing loss, and chronic
otitis media
- Obesity and nutrient deficiency
-Malabsorption
-probably linked with celiac disease) due to intestinal
damage
- Some has lack of vitamin B12, folic acid and zinc
- Need for antioxidants i.e. vitamin E
• Reproduction
• Women with DS are fertile and may become pregnant.
• Nearly all males with DS are infertile due to impaired
„spermatogenesis‟.
• Skeletal abnormalities
• Atlantoaxial instability
• flat foot
• Dysgenesis of middle phalanx in little finger,
• narrow maxilla
• Clindactyly.
 screening
• All women should be offered screening for Down
syndrome in their 2nd trimester by means of 4 maternal
serum tests (free βhuman chorionic gonadotropin [β-
hCG], unconjugated estriol, inhibin, and αfetoprotein).
This is known as the quad screen; it can detect up to
80% of Down syndrome.
• FIRST TRIMESTER • Free beta HCG • fetal nuchal
translucency (NT) thickness that can be done alone or in
conjunction with maternal serum β-hCG and pregnancy
associated plasma protein-A (PAPP-A).
 screening
• Integrated screen :If both 1st- and 2ndtrimester
screens are combined using NT and biochemical
profiles, the detection rate increases to 95%.

• Detection of cell-free fetal DNA in maternal plasma

is also diagnostic and replacing conventional 1st-
and 2nd-trimester screens. •
 Management
• Growth measurements: should be plotted on the
appropriate growth chart for children with DS. • This
will help in prevention of obesity and early diagnosis
of nutritional and hormonal problems.
• Cardiac disease– All NB with DS should be evaluated
by cardiac ECHO for CHD in consultation with
pediatric cardiologist.
• Hearing– Screening to be done in the newborn
period, every 6 months until 3 yrs of age and then
annually.
• Eye disorders - An eye exam should be performed in
the newborn period or at least before 6 months of age
to detect strabismus, nystagmus, and cataracts.
• Thyroid Function – Should be done in newborn
period and should be repeated at six and 12 months,
and then annually.
• Celiac Disease – Screening should begin at 2 yrs.
Repeat screening if signs develop.
• Hematology – CBC with DLC at birth to evaluate for
leukemia.
• Atlanto-axial instability – X ray for evidence of AAI
or sub-luxation at 3 to 5 years of age.
• Alzheimer’s disease – Adult with a Down Syndrome
has earlier onset of symptoms. When diagnosis is
considered, thyroid disease and possible depression
should be excluded.
• Rehabilitation
 Counseling
• Chromosome analysis is indicated in every person
suspected of having Down syndrome.
• Translocation :
– parental chromosome studies must be performed to
determine whether one of the parents is a
translocation carrier, which carries a high
recurrence risk for having another affected child.
 Recurrence risk
• Trisomy 21(nondisjunction): Random risk as general
population (1:700)
• New translocation (mutation): Random risk as general
population
• Inherited translocation (13,14,15,22): If mother is
carrier 5-7%
• Inherited translocation (21): If mother is carrier 100%
• If mother is Down syndrome risk is 50%
 Prognosis
• Avarage life span is 25yrs. To 50 yrs.
• Most likely cause of death is CHD, atlanto-axial
instability, MR, rec. infections and Leukemia.
• Survival is better for males
• Multi-disciplinary team of care and rehabilitation
centers.
Thank You