Chromosomal abnormalities Chromosomal anomalies down syndrome turner syndrome klinefelter syndrome edward syndrome patau syndrome nondisjunction mutation cell membrane disorders tight junctions autosomal recessive thalassemia

1. Cell structural &
Chromosomal
abnormalities
Dr. Irtaza Rehman
(Author of the book The Extraordinary Life)

3. Learning objectives
• To understand the defects of cell membrane
• To understand the Genetics of cell
• To understand the inherited and genetic
disorders
• To understand clinical features and diagnosis of
Down syndrome

4. Clinical
importance
of cell
membrane
• Acts as a barrier
• Bw the cell, the
environment, &
the subcellular
compartments

5. Clinical
importance
of cell
membrane
Tight junctions
• TJ is a protein complex bw 2 cells
that creates a seal to prevent
any leakage of the content
through the cell membrane
• Defects: Intestine(Crohn’s
disease), BBB(Multiple sclerosis),
Eye(diabetic retinopathy)

6. Crohn’s Disease Multiple sclerosis

7. • Maintains homeostasis
• By balancing pH
• Temperature
• Glucose(sugar intake)
• Water balance
Clinical importance of cell membrane

8. • Na-K pump defect
• Decreased (Cardiac failure) in myocardium
• Increased (Hypertension) in renal tubules 
increased Sodium reabsorption
Clinical importance of cell membrane

9. Ion channel diseases/Channelopathies
• Due to mutations of genes encoding the ion
channels
• Sodium channel diseases: Muscle spasm
• Potassium channel diseases: Cardiac failure,
epileptic seizures in newborn
• Chloride channel dysfunction: Renal stones,
cystic fibrosis

10. Human genome
• Complex nuclear genome + simpler mitochondrial
genome
• 30,000 genes (27000 protein coding + 3000 RNA
coding genes)
• 2% coding DNA + 98% non coding DNA
• Epigenetic control: Chemical modification of DNA
(methylation) & histones (acetylation,
phosphorylation)

11. Non coding DNA
• Satellite DNA
• Minisatellite DNA
• Microsatellite DNA
• Transposons (Jumping genes)

12. Q. Double Helix
DNA held
together by?
A. Covalent Bonds
B. Ionic bonds
C. Hydrogen bonds
Ans. C

13. • A DNA: Right handed helix with 11 bp/turn
• B DNA: Right handed helix with 10 bp/turn
• Z DNA: left handed helix with 12 bp/turn
• In humans: B DNA under physiological
conditions.

14. Q. Which amino acid
is NOT coded by
several codons?
Ans. Methionine (AUG)
Start codon

15. Q. What do you know
about chargaff’s rule?
• The ratio of purine to
pyrimidine bases in
the DNA molecule is
always around 1
(G + A/T+C=1)

16. Junk DNA
• Old concept: portions of DNA sequence of a
chromosome or genome for which no function
has been identified
• 80 to 90%
• Most sequences with introns

17. • Latest concept: Capable of repairing broken
strands of DNA
• Advantageous new genes may emerge
• Regulation of gene expression/gene diversity
• Specialized role in cell behavior
Junk DNA

18. • Nucleosomes contains 4
types of histones (H2A,
H2B, H3, H4) The Core
histones
• Histones associate to form
histone octamer
• Basic proteins in chromatin
Arginine and Lysine

19. Mutations in DNA
• a change in the DNA sequence of an organism

20. Q. Which one
causes least
change in DNA?
• A. Missense
• B. Silent
• C. Frameshift
• D. Nonsense
• Ans. Silent
Q. Which one
causes greatest
change in DNA?
• A. Missense
• B. Silent
• C. Frameshift
• D. Nonsense
• Ans. Frameshift

22. Deletion
Protein may be shorter or longer
Insertion or deletion of nucleotides not
divisible by 3

23. What am i?
• I am A specialized
nucleotide sequence that
binds to the mitotic spindle
• A pair of protein complexes
‘kinetochores’ forms at me
& one kinetochore is
attached to each sister
chromatid Ans. Centromere

24. Barr body
• Inactivated X
chromosomes seen in
female somatic cells are
called Barr-bodies which are
present adjacent to the
nuclear membrane

25. Telomere
• a region of repetitive
DNA sequences at the
end of a chromosome.
• Telomeres protect the
ends of chromosomes
from becoming frayed
or tangled.
• Becomes shorter after
each cell division
Telomerase adds DNA to telomeres
Helps keep them alive
Utilized by stem cells/neoplastic cells
Play role in aging and cancer

26. Telomere

27. Arms of chromosomes
• The position of the centromere
forms the arms of
chromosomes.
• P (petit arm)  Shorter
• Q (queue)  Longer

28. Q. Type of
chromosome in which
centromere is located
as in Y chromosome.
Ans. Telocentric

29. Types of chromosomes

30. Errors occurring during meiosis
Variation in normal diploid # of chromosomes
Aneuploid
From non-disjunction
Chromosomes not a multiple
of haploid #(23)
Polyploid
Chromosomes more than 2
times the haploid number
Incompatible with life

31. Associated with advanced maternal age

33. Q. Identify the mutation
Inversion

35. Q. Identify the mutation
Deletion 5p

36. Cat Cry Syndrome/Cri du chat
Deletion 5p high-pitched cry

37. Isochromosomes
• 2 chromosomes with
2 short and 2 long
arms
• Due to transverse
division not
longitudinal

38. Ring chromosomes
 Occurs during
development
 Ends are lost
 Two arms fuse to
form a closed circle

39. Q. What am i?
• I am a diagram predicting the
outcome of a mating between
individuals with different genotypes
• I provide a graphic representation of
all possible genotypes of the offspring
of the cross.
• I determine the frequency of offspring
affected by various modes of
transmission.
Punnet Square

41. Q. Guess the inheritance.
• Every generation of the pedigree is likely
to be affected.
• The likelihood of affected offspring is
50%, regardless of sex.
• One affected parent (likely a
heterozygote) mates with a normal
individual, resulting in transmission.
Ans. Autosomal dominance

42. Autosomal dominance

43. Autosomal dominant disorders
• Huntington disease
• Marfan syndrome
• Neurofibromatosis
• Hypercholesterolemia

44. Thalassaemia
Q. Identify the inheritance?
Autosomal
Recessive
Consanguinity
increases
occurrence
Male & Female
equally
affected

45. Kashif Iqbal Thalassaemia center

46. Autosomal recessive disorders
• Cystic fibrosis
• Phenylketonuria
• Sickle cell anemia
• Hemochromatosis

47. Q. Can heterozygous
female ever show signs
of X-linked recessive
disorder?
• Ans. Yes, if the X chromosomes with normal
dominant gene are inactivated in a large # of
cells. The female will have large # of cells in
which one active X chromosome has the
abnormal recessive gene (Xr
)

48. X-linked recessive

49. Hemophilia A
Clotting factor VIII
deficiency
Life threatening
bleeds from minor
trauma
X-linked recessive

50. Duchenne muscular dystrophy
X-linked
recessive

51. X linked dominant disorders
• Fragile X syndrome
• Alport syndrome
• Hypophosphatemic rickets

52. Only I can
transmit
the
disease
Mitochondrial Inheritance
Mitochondrial myopathies
Leber hereditary optic
neuropathy
(LHON)

53. Q. Amniocentesis is performed on a patient
at 16 weeks gestation because of her age
(she is 36). The final report to the physician
says that the fetus has a 45X/46 XX
karyotype, with the 45 X cell line making
up 90% of the cells examined. The fetus will
most likely have phenotypic features of
which of the following symptoms?
A. Fragile X syndrome
B. Turner syndrome
C. Down syndrome
D. Angelman syndrome
Ans. Turner Syndrome

54. Turner syndrome 45X0 Monosomy
Zero Barr Bodies Gonadal dysgenesis
Infertility

55. Klinefelter Syndrome 47 XXY
• At Puberty: Hypogonadism, failed secondary sexual
characteristics, female body habitus.
• Intellectually disable, problems with reading,
writing, spelling, or math
• Tendency to be shy and sensitive
• Tall stature, gynecomastia
• Infertility, Increased belly fat

56. Did you know? Tom Cruise is rumoured
to have klinefelter syndrome

57. Autosomal Trisomies
• Down syndrome  21
• Edward syndrome  18 (Election age = Edward)
• Patau syndrome  13 (Puberty age = Patau)

58. Patau Syndrome
• C  Cleft palate/lip
• R  Renal abnormalities
• A  Aplasia cutis
• M  Mental retardation, Micropthalmia
• P  Polydactyly

59. Edward syndrome
• M  Micrognathia
• R  Renal abnormalities
• E  Eighteen Trisomy
• D  Digit overlapping
• W 
• A  Absent intellect
• R  Rocker bottom feet
• D  Diseased heart

60. Case
• History
Parents of a 5-Year-old boy present to a clinic of a
tertiary care hospital with complains that the child has
not yet started walking unsupported or speaking, & has
looks very different from his siblings. On asking parents
also report delayed sitting, & that he was also a slow
learner. He could not feed himself & was not yet toilet
trained also. He was born about 10 year later than their
last child when mother’s age was 45 years.
• All other family members were normal.

61. • On Examination
He appeared shorter for his age and plump. He had a
small head; tongue appeared larger because it
appeared to be protruding out of the mouth all the
time. He had depressed nasal bridge and small ears
with folded ear pinna. He could barely talk but could
communicate with gestures. Hands were small with
fifth finger bent towards the fourth and there was only
single palmar crease
Case

62. • His investigations showed
• EEG: Recurrent Seizure
discharges.
• ECG: Prolonged QRS complex.
• Blood sugar: 205mg/dl
All other investigations were
normal.
Case

63. Down Syndrome

64. Down Syndrome

65. Down Syndrome

66. Down Syndrome
Smaller size head

67. High arched palate
Down Syndrome

68. Down Syndrome

69. Excess skin
at nape of
the neck
Down Syndrome

70. Flat Nasal bridge
Down Syndrome

71. Down Syndrome

72. Down Syndrome

73. Down Syndrome
Gap
between
1st 2 toes

74. 5 A’s of Down Syndrome
Advanced maternal age
Atresia (duodenal)
ASD
Alzheimer disease
AML (<5 years of age)/>5 years of age)
Down Syndrome

75. Down Syndrome
Increased
risk of
umbilical
hernia

76. Down Syndrome

77. Down Syndrome

78. Down Syndrome

79. Quad screening
• Increased: B-HCG, Inhibin A
• Decreased: Estriol, AFP
Down Syndrome

80. Q. Most common
inherited cause of
intellectual
disability?
• A. Fragile X syndrome
• B. Klinefelter syndrome
• C. Turner syndrome
• D. Down syndrome
Ans. A

81. • Social/physical issues
• Delays in speech
• Difficulties dealing with hygiene
• Sexual/physical abuse
• Psychological problems
Down Syndrome

82. Down Syndrome

83. A2-year-old boy with Down syndrome
requires intubation in the intensive
care unit due to difficulty breathing.
He is afflicted with congenital heart
disease associated with the disease,
and he dies shortly after admission.
What is the most common genetic
cause of Down syndrome?
(A) Meiotic nondisjunction
(B) Autosomal dominant inheritance
(C) X-linked recessive inheritance
(D) Decreased maternal age
(E) Monosomy21 Ans. A

85. Jazakumullahu Khair ♥
(May ALLAH swt reward you with goodness)