genetics for medical undergraduates

1. Chromosome disorders
 Number
Extra chromosome
Missing chromosomes
 Structure
Translocations
Inversions
Deletions
Duplications
Ring chromosomes
Isochromosomes
MOSAICISM / CHIMAERISM

2. CHROMOSOMAL ABNORMALITIES
NUMERICAL STRUCTURAL
Aneuploidy Polyploidy
Monosomy
Trisomy
SYNDROMES
Turner
Down
Edwards
Patau
Triploidy
Tetraploidy
Embryo usually
aborts
Deletion
Cri-du-
chat
Inversion
Miscarriages
increase
Duplication
Insertion
Translocation
Abnormal
segregation in
carriers of
translocation or
inversion
Gene
disruption
Leukemia
Lymphoma
2

3. Numerical Chromosome Abnormalities
Euploidy = having a complete chromosome
complement, with no additions or deletions, i.e. the
“normal” state
Polyploidy = having extra full sets of chromosomes, ex.
tetraploid
Aneuploidy = having any extra or missing genetic
material, no matter how much
Trisomy = having an extra member of one chromosome
pair, ex. extra chrom 21 = Down syndrome = trisomy 21
Monosomy = having only one member of a chromosome
pair, ex. female missing an X = Turner syndrome =
monosomy X

4. Chromosome Nondisjunctions Lead To
Monosomies And Trisomies

5. Chromosome Nondisjunctions Lead To
Monosomies And Trisomies

6. Chromosome
Nondisjunctions
Lead To
Monosomies And
Trisomies
Nondisjunction can
occur during mitosis
and be a somatic
mutation

7. Causes of Non disjunction
 Advancing maternal age
 Radiation
 Delayed fertilization after ovulation
 Chemicals, Smoking, Alcohol, Oral
contraceptive
 Fertiliy drugs, pesticides
 Genetic control

8. The Probability
Of
Nondisjunction
Increases With
Age
It is believed that a
reduced ability to
recombine during
prometaphase I
leads to an
increased
frequency of
nondisjunction

9. In Humans, Only Trisomy 21
Produces Viable Offspring

10. DISORDERS OF CHROMOSOME
NUMBER
Down’s syndrome (MONGOLISM)
(Trisomy 21) 47 chromosomes
Clinical features:
Incidence 1/700
2/3 of fetus spontaneously abort
Trisomy 21 in 94% of cases with extra
chromosome from mother
mostly(95%)
Risk correlate with maternal age
<25 y/o 1/1600
>40 y/o 1/80
2% are mosaics

11. Clinical features
 Mentally retarded IQ.25-75
 Poor growth, short stature
 May have heart and stomach illnesses
 Small head circumference
(brachycephaly)
 Hypotonia without weakness
 Protruded tongue, epicanthic fold
 Small ears, slopping palpebral fissures
 Small up turned nose, depressed
nasal bridge.
 Hands are short and broad. Simian

12. Genotype: 47+XY or 47+XX
 Non disjunction in the first meiotic division, the
father
contributing the extra chromosome in 15% of
cases.
 Mosaic due to non disjunction in an early
zygotic division.
 Translocation in 4% of cases.
Recurrence risk : 1-3% if father carrier
15% if mother is a carrier .Increases with
mothers age
Life Span: Mean age:16 yrs.
Develop Alzheimers disease.
Counselling:
Amniocentesis

13. 13

14. EDWARD,S SYNDROME
 Trisomy of chromosome 18
 Incidence 1/8000
 Spontaneous abortion, >90% dead in 1st year
 CLINICAL FEATURES
 Retarded growth & development
 Small face with prominent occiput
 Small sternum and pelvis
 Flexion deformity of the finger
 VSD and horseshoe kidney
 Hypertonia, Small chin
Low set malformed ears
 Child holds fingers in typical way
 Heart defects; VSD, PDA
 Genotype:Trisomy 18
 Counselling: Most babies die in the first year and many within the first

15. 15

16. Trisomy 13: PATAU,S SYNDROME
Incidence:1 in 5000 live births.
Most spontaneous abortion
50% die within first month, very
few survive beyond first year.
There are multiple dysmorphic
features.
Genotype: Trisomy of
chromosome 13
Mosaicism & Robertsonian
translocation
in rare cases.
Counselling;
Small risk of recurrence
Increases with advanced maternal

17. Clinical features
Severe physical & mental
retardation
Small skull & eyes.
Cleft lip & cleft palate
Extra finger or malformed
thumb
Malformations of CVS,
CNS and Excretory systems

18. Incidence: 1 in 5000 female births
99% of Turner syndrome embryos are
spontaneously aborted.
Clinical features:
Individuals are very short, infertile. webbed neck
Broad chest, widely spaced nipples and
underdeveloped
breasts
Lack of expected secondary sexual
characteristics
Coarctation of the aorta, VSD
Abnormalities of urinary system
IQ and lifespan are unaffected

19. Turner’s syndrome – only 45 chromosomes,
sex chromosome (X) is missing
Girls affected – short, slow growth, heart problems

20.  Genotype: Monosomy of X chromosome
 Mosaisim (15%) 45XO/46XX,
 Isochromosome 46,X,i(Xq)
 Ring chromosome
 Sex chromatin is negative
 Counselling :
 Oestrogen replacement therapy
 Remove gonads
 Invitro fertilization
 Recurrence risk is 1-2%

21. XXX Syndrome
 0.1% of all females
 Trisomy X
 Female
 Little or no visible differences
 Tall stature .Normal reproductive life
Reduction in IQ ,Learning disabilities
 Genotype:
XXX chromosomes
2 Barr bodies
Females with > 3X chromosomes can also
survive
Sterile, severe mental retardation, many
phenotypic effects

22. Klinefelter’s syndrome
47 chromosomes
Extra X chromosomes (XXY)
Genotype: Karyotype 47,XXY
Mosaicism: 46XY/47XXY
Barr body present
Incidence : 1 in 1000

23. Kleinfelter’s syndrome 47,XXY
Clinical features:
Testes are small and fail to
produce normal levels of
testosterone which leads to
gynaecomastia in about 40% of
cases
Poorly developed secondary
sexual characteristics. No
spermatogenesis.
Taller and thinner than average
and may have a slight reduction
in IQ.
Many Kleinfelter males lead a
normal life.
Extreme forms of Kleinfelter's

24.  XYY Syndrome
 Incidence: 1 in 1000
 Normal male traits
 Often tall and thin,10 - 15 points reduction in IQ compared
to sibs
Associated with antisocial and behavioral problems
Genotype: 47,XYY
Additional Y chromosome due to non dysjunction at
Meiosis II

25. DISORDERS OF CHROMOSOME
STRUCTURE
 Deletion
 Duplication
 Inversion
 Translocation
 Ring Chromosomes
 Isochromosomes

Translocation
Deletion
Insertion
Inversion
Isochromosome
Ring
chromosome
Derivative
chromosome

26. Structural Chromosome Abnormalities--
Deletions
 Deletions are when one
or more nucleotides are
removed from the DNA
sequence.
 This causes a shift in the
reading sequence of DNA
and can produce a
completely different
protein strand than the
original.
 Deletions result in Frame
shift Mutations
TYPES
MICROSCOPIC OR CHROMOSOMAL DELITIONS
 CRI-DU-CHAT SYNDROME
SUBMICROSCOPIC MICRODELITIONS

27. Chromosome 22q11.2 deletion syndrome
 Small deletion of band q11.2 on long arm of chromosome 22.
 1 in 4000 births
 Congenital heart defects ,palatal abnormalities, facial dysmorphism,
developmental delay,T-cell immunodeficiency and hypocalcemia
 High risk for schizophrenia and bipolar disorder

28. Cri-du-chat syndrome
Incidence : 1 in 50.000 births
 Deletion of material on 5th
chromosome
 Clinical features :
Characterized by the cat-like cry made
by cri-du-chat babies due to under
development of larynx.
 Varied levels of metal and physical
retardation
 microcephaly

29. Angelman ,s syndrome
SUBMICROCOPIC MICRODELITION
Cannot be visualised by karyotype.
Needs FISH studies.
CLINICAL FEATURES
Severe mental retardation
Inappropriate laughter
Decrease pigmentation of choroid or iris (pale
blue eyes)
Ataxia and jerky eye movements
Severe speech problem
Deletion of b15q11q13, maternal in origin

30. Prader-willi syndrome
 Chromosome no 15 is affected
 Clinical features
 (A fat red faced boy in state of
somnolency)
 Early hypotonia
 Obesity
 Short stature as adult
 Almond shaped blue eyes
 Mental retardation (mild to
moderate)
 Narrow hands

31. Structural Chromosome Abnormalities--
Duplications

32. Duplications And Deletions Can
Arise From Unequal Crossovers
Repeated sequences can cause uneven alignments

33. PERICENTRIC: has one
breakpoint in the p arm and
one in the q arm
Structural Chromosome Abnormalities--
Inversions
PARACENTRIC has both
breakpoints in the same arm

34. Structural Chromosome Abnormalities
Ring Chromosomes
Ex. Female with ring chrom 4, breakpoints p23.2 and q 12.4 =
46,XX,r(4)(p23.2q12.4)
A mutation event which
removes both
telomeres can be
repaired by sealing the
ends together forming a
ring chromosome.
This will be deleted for
genes at both ends of
the chromosome.
The symptoms will
depend on the extent of
the deletion. Ring
chromosomes are

35. A chromosome can split "the
wrong way" in mitosis (or
meiosis II) so that both long
arms remain attached and
move to one pole, and both
short arms to the other
pole.
The consequence is the
formation of an
isochromosome. These are
simultaneously duplicated
for the genes in the
retained arm and deleted
for the genes in the other.
Isochromosomes

36. Structural Chromosome Abnormalities—
Reciprocal Translocations

37. Structural
Chromosome
Abnormalities
Reciprocal
Translocations
46,XX, t(1;18)
Note that the two
chromosomes 1
are of unequal
size, as are the
two chromosomes
18

38. Structural Chromosome Abnormalities
Robertsonian Translocations
p arm of acrocentric chromosome
contains hundreds of copies of
rRNA gene, so losing two p arms
does not cause an abnormal
phenotype.
A Robertsonian translocation is
considered a single chromosome.
Acrocentric chromosomes 13, 14,
15, 21 and 22 form Robertsonian
translocations
If you have 5 Robertsonian
translocations, and don’t lose all
of the p arm material from all

40. Robertsonian Translocations Can Result In
Trisomies
The Robertsonian translocation is actually two fully
functioning chromosomes
It also has two centromeres,
one dominates over the other.
when it comes time of pulling
one set of chromosomes into
each daughter cell during
anaphase of meiosis I
When the cell divides during
meiosis I, the Robertsonian
translocation is treated as if it
was a single chromosome,
and the daughter cell does not
realize it has obtained a copy

41. Important Issues Pertinent
To Structural Rearrangements
Balanced = No DNA was lost
when the chromosomes
broke
The individual has all
his/her genes
Rarely causes a genetic
disorder
Will only cause a genetic
disorder if
one of the breakpoints
interrupts a gene

42. Unbalanced = DNA was
lost
when the chromosomes
broke
The individual is missing
one or
more of his/her genes
Often causes a genetic
disorder
Severity of effect is often
proportional to the amount
of

43. Important Issues Pertinent
To Structural Rearrangements
Are The Individual's Children At Risk?
 A balanced rearrangement that does not cause a
genetic disorder in the individual can still pose a risk
for the individual's offspring
The chromosomes cannot line up evenly during
meiosis
This may result in the egg or sperm having an
unbalanced genetic complement, i.e. missing
material, extra material, often a combination of both