Numerical and structural chromosomal Aberrations

(Autosomal)
Clinical Biochemistry, University of Tabuk.
Dr. Ashraf

Md Ashraful Islam MBBS, MD, PhD

( USMLE completed)
Assistant Professor
Clinical Biochemistry
Medical Genetics Coordinator
a.islam@ut.edu.sa
0506487454
At the end of this lecture, students should be able to:

 Describe numerical and structural aberrations of autosomes.

 Identify common syndromes of numerical and structural aberrations of
autosomes (e.g., Mongolism).

Includes:

 Types of numerical aberrations (euploidy and aneuploidy).

 Forms of structural aberrations (translocation, deletion, duplication, inversion,
shift, isochromosome formation and ring formation).
 Chemira and mosaicism.
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Gene therapy
Basic Definition
• Chromosomes, DNA and genes
• Chromatides, and centromere
• Arms of a chromosome (p and q)
• Karyotype
• Autosomes and sex chromosomes
• Genotype and phenotype
Karyotype
• It is the set of chromosomes of an individual.
• It is the systematized arrangement of the chromosomes of a single cell.
• Chromosomes are arranged in groups A to G according to their shape & size.
Short arm and long arm
 Introduction:
• In the human cell, 23 pairs (diploid number); of these 23 pairs,
22 are similar in both sexes and are called the autosomes.
The remaining pair is called sex chromosomes : XX in the
female cells and XY in the male cells .
• The genotype is the set of genes the individual carries.
• The phenotype is the external appearance of an individual as
determined by his genotype.
 Genetic Disorders
• Chromosomal abnormalities
• Single gene disorders
• Multifactorial (polygenic) inheritance
• Unusual patterns e.g. mitochondrial
inheritance
• Due to teratogens
 Chromosomal Abnormalities
Numerical
Polyploidy: Multiple of the haploid (> Diploid)
Aneuploidy: Abnormal number

Structural.
Translocation
Deletion
Others
• They are a very common cause of early spontaneous miscarriage.
• Usually, but not always, cause multiple congenital anomalies and
learning difficulties.
 Numerical Aberration
• Autosomal
- Trisomies: 1 ch extra (e.g. trisomy 21-13-18)
- Monosomies: 1 ch is missing
• Sex chromosome
- Klinefilter syndrome (47, XXY male)
- Turner syndrome (45, XO female)
Karyotype of a normal male
Karyotype of a normal female
Karyotype of a normal male
Overlapping of the fingers in
Edwards' syndrome
 Structural abnormalities
1) Translocation :
the transfer of a chromosome or a segment of it to a
non-homologous chromosome.
2) Deletion : loss of a portion of a chromosome.
3) Ring chromosome
4) Duplication : extra piece of a chromosome.
5) Inversion : fragmentation of a chromosome followed
by reconstitution with a section inverted.
6) Isochromosomes : division of chromosome at
centromere transversely instead of longitudinally
Structural abnormalities
Structural abnormalities
Structural abnormalities
 Structural Abnormalities

Inversion

Deletion Duplication
 Structural Abnormalities

Isochromosome

Ring chromosome
 Reciprocal translocations
• An exchange of material between two different chromosomes is called a
reciprocal translocation. When this exchange involves no loss or gain of
chromosomal material, the translocation is 'balanced' and has no
phenotypic effect.
• Balanced reciprocal translocations are relatively common, occurring in 1 in
500 of the general population.
• Finding a balanced translocation in one parent indicates a recurrence risk
for future pregnancies and antenatal diagnosis by chorionic villus sampling
or amniocentesis should be offered as well as testing of relatives.
 Structural abnormalities

Robertsonian Translocation

Reciprocal Translocation
Reciprocal Translocation
Robertsonian Translocation
Deletion syndromes
 When to suspect chromosomal
abnormalities?
• Abnormal features
* coarse facies * Mongoloid eye
* Low set ears * Micrognathia/cleft lip & palate
* Simian crease * Clinodactyly
• Mental retardation Do chromosomal analysis
• Ambiguous genitalia Do chromosomal analysis
• Delayed puberty:
Klinefelter syndrome and Turner syndrome
Low set Ears
Clinodactyly
 Genetic types (Cytogenetics)
(1) Non-disjunction : “ 95 % of cases”
• It is due to failure of disjunction of the 2
chromosomes of the pair No 21 during division, the
extra 21 chromosome is separate and so total no. in
cell is 47.
• Incidence is higher with increasing maternal age & so
it is age-dependent
Non-disjunction
 Genetic types (Cytogenetics)
(2) Translocation : “ 4 % of cases”
• The extra 21 chromosome is translocated (attached)
to another chromosome e.g. (15/21) so total no. of
chromosomes is 46 but the genetic material is that
of 47 chromosomes .

• Incidence is usually in young mothers & risk of

recurrence is high & mother is called translocation
carrier
Figure 8.4 Translocation Down's syndrome. There is a translocation between
chromosomes 21 and 14 inherited from a parent
 Down syndrome Translocation carrier

• One parent contains a 14/21 translocation and has

only 45 chromosomes, and is a phenotypically
normal carrier.
• 1/4 of the individual's gametes will have almost 2
copies of chromosome 21.
• The resulting zygote has 46 chromosomes, but
almost 3 copies of chromosome 21, and exhibits
Down syndrome.
(3) Mosaicism : “ 1 % of cases”

Some cells are normal (46 chromosomes) &

others are trisomic (47 chromosomes)

Clinical feature are less evident & M.R. is mild

Brushfield spots
Simian Crease, Trisomy 21
Klinefelter syndrome
 Turner syndrome
Cytogenetics: 45, XO, FEMALE
Incidence: 1/5000
Features
• Lymphedema of hands and feet in newborn
• Short stature
• Webbing of neck
• Wide carrying angle
• Gonadal dysgenesis (1ry amenorrhea)
• Renal anomalies and cardiac anomalies
Turner Syndrome
 Single gene disorders
• Every trait is represented by 2 genes, one from the father and the other
from the mother . When the 2 genes for any given trait are similar, the
person is homozygous for this trait . If the 2 genes are different, the
person is heterozygous.
• A dominant gene expresses itself whether homozygous or heterozygous
while recessive gene expresses itself only when homozygous .
• Family pedigree means summarizing genetic data that is collected by
observing the patterns of transmission of traits within the family
Fragile X syndrome
 These unusual findings are explained by the nature
of the mutation, which occurs in 'pre-mutation' and
'full mutation' forms.
 Norma copy of gene < 50 copies of CGG
trinucleotide.
 Genes with premutation contain 55-199 copies.
 Genes with full mutation contain > 200 copies of
CGG.
 This big number affects gene function, leading to
learning disabilities.
Trinucleotide repeat expansion mutation

FMR1 (fragile X mental retardation 1) is a human gene that codes

for a protein called fragile X mental retardation protein, or FMRP
Trinucleotide repeat expansion mutation
A child with fragile
X syndrome. At this
age, the main
physical feature is
often the prominent
ears.
 Fragile X syndrome
Clinical findings in males in fragile X syndrome
• Moderate-severe learning difficulty (IQ 20-80, mean 50)
• Macrocephaly
• Macro-orchidism - postpubertal
• Characteristic facies - long face, large everted ears,
prominent mandible and broad forehead, most evident in
affected adults.
• Other features - mitral valve prolapse, joint laxity,
scoliosis, autism, hyperactivity
•Fragile X syndrome is the second most common
genetic cause of severe learning difficulties after
Down's syndrome.