for Undergraduate Medical Students (MBBS)

1. Genetic Disorders
Dr.CSBR.Prasad, M.D.

2. Karyotype
 Each arm is divided into 2 or more
regions
 Each region is divided into bands and
sub bands
 They are numbered from centromere
outwards ex. Xp 21.2

4. Numerical & Structural
Abnormalities

5. 1- Numerical Abnormalities

6. Numerical Abnormalities
• Diploid (2n)
• Polyploid (2n+….)
• Euploid (exact multiples of n)
• Autopolyploidy
• Allopolyploidy
• Aneuploid
• Hyperaneuploidy
• Hypoaneuploidy

7. Numerical Abnormalities
• Diploid
• Polyploid
• Euploid (exact multiples of n)
• Autopolyploidy
• Allopolyploidy
• Aneuploid
• Hyperaneuploidy
• Hypoaneuploidy

8. Numerical Abnormalities
• Diploid
• Polyploid
• Euploid (exact multiples of n)
• Autopolyploidy
• Allopolyploidy
• Aneuploid
• Hyperaneuploidy
• Hypoaneuploidy

9. Numerical Abnormalities
• Diploid (2n)
• Polyploid (2n+….)
• Euploid (exact multiples of n)
• Autopolyploidy
• Allopolyploidy
• Aneuploid (addition of 1 or 2 chr)
• Hyperaneuploidy (2n+1, 2n+2)
• Hypoaneuploidy (2n-1, 2n-2)

10. Mechanism of Aneuploidy
 Non disjunction – Failure of chromosome to
separate normally during cell division
result in monosomy or trisomy
 Anaphase lag - One chromosome fail to
reach the pole of dividing cell at the same
time and is left out of nucleus of daughter
cell
 Mosaicism – Individual has 2 or more types
of cell lines derived from same zygote
ex. cancers

13. 2- Structural
abnormalities

14. Structural abnormalitiesStructural abnormalities
Deletion
Inversion
Duplication
Translocation
Ring chromosome
Isochromosome

15. Structural abnormalities
 Translocation – Transfer of a segment of
one chromosome to another non-
homologous chromosome
1. Balanced translocation – When two
fragments of chromosomes exchange
materials without any loss of genetic
materials. ex. Philadelphia chromosome –
t(9:22) (q34:q11)
2. Robertsonian translocation

16. Structural abnormalities -
Translocation
Balanced translocation

17. Structural abnormalities
2. Robertsonian translocation – When
two acrocentric chromosome lose
their short arm and fuse at the
centromere so that eventually the
cell is left with 45 chromosomes.

18. Robertsonian
Translocation

19. Structural abnormalities
Translocation: Ex: Acute Myelogenous Leukemia
Philadelphia chromosome t(9,22)

20. Structural abnormalities
 Deletion
 Loss of part of the DNA from a
chromosome. Deletion may be from
terminal portion/ Middle portion

21. Deletion – Terminal
deletion of short arm

22. Deletion – Terminal
deletion of long arm

23. Deletion –Deletion
of long arm

24. Can you give one best
example for deletion
resulting in disease?
Alfa-Thalassemia

25. Structural abnormalities
Ring chromosome: When both ends of a
chromosomes are lost and the damaged
ends join together, they form Ring
chromosomes

26. Deletion –
Ring
chromosome

27. Diseases in which ring
chromosomes are seen
include:
Some tumors of adipose tissue
Fanconi’s anemia

28. Structural abnormalities
Duplications: Ex: Fragile X syndrome
 The most common form of mental
retardation
The X chromosome have over 700
repeats due to duplications (Normal
upto 29)
Affects 1:1500 males, 1:2500 females

29. Structural abnormalities
Duplications: Ex: Fragile X syndrome

30. Structural abnormalities
 Isochromosome formation result when the
centromere divides in a tranverse plane
rather than in a normal long axis of the
chromosome
Ex. One with 2 short arms & one with 2 long
arms

31. Isochromosome

32. Structural abnormalities
 Inversion: Rearrangement that
involves two breaks within a single
chromosome with reincorporation of
inverted segment
 Paracentric
 Pericentric

33. Inversion – (long
arm)
Paracentric Pericentric

34. Mutation
 Permanent change in the DNA
 Mutation in germ cell – Inherited
diseases
 Mutation in somatic cells – Cancer,
congenital malformation

35. Mutation
 Genomic Mutation – Monosomy/
trisomy
 Chromosomal Mutation –
rearrangement of genetic material
with visible structural changes in chr.
 Gene Mutation – Submicroscopic
1. Point mutation
2. Frame shift mutation

36. Mutation
 Point mutation – single nucleotide
base is substituted by different base.
e.g. sickle cell disease – glutamic acid
replaced by valine at 6th
position from
the aminoterminal of beta globin
chain of Hemoglobin

37. Mutation
 Frame shift mutation
 One or two base pairs may be inserted/
deleted from the DNA, leading to
alterations in the reading frame of the
DNA strand

38. Frameshift Mutation
(1-2 bp(s) deletion) (1-2 bp(s) insertion)

39. Insertion

40. Duplication

41. Variation in number

42. Down’s Syndrome

43. Down’s Syndrome
 Trisomy 21, 47 XY + 21
 Most common chromosomal disorder
1 in 700 live births
 Due to non disjunction Or
Robertsonian translocation
 Parents – Normal karyotype
 Risk factor Mother over 35 years

44. The fertilization of a genetically abnormal egg carrying an extra
chromosome 21 (orange) by a normal sperm (green) produces an embryo
with Down syndrome (purple).

45. Trisomy 21 -- Down’s syndome

46. Click to see animation on Non-Disjun

47. Down’s Syndrome
 Clinical Features
 Major cause of mental retardation IQ 25-50
 Very gentle, shy & friendly
 Diagnosed at birth by “mongol” look – Flat
facial profile, oblique palpebral fissure,
epicanthic folds
 40 % of patients – CHD
 ASD, Ostium primum, A-V valve
malformation, VSD

49. Down’s syndromeDown’s syndrome
Normal Mongols Down’s baby
With Mongoloid look

50. Down’s syndrome

51. Down’s syndromeDown’s syndrome
Normal hand Simian crease

52. Down’s syndromeDown’s syndrome
Simian creaseSimian crease

53. Down’s syndromeDown’s syndrome
Simian crease

54. Down’s syndrome

55. Down’s syndrome
Umbilical hernia

56. Down’s syndromeDown’s syndrome

57. Down’s Syndrome
 Acute Leukemia – 10 to 20 fold ^ risk
 Alzheimer’s disease < 40 years of age
 Abnormal immune response – Infection
 Simian crease, Hypotonia, Umbilical hernia

58. Down’s Syndrome
 Acute Leukemia – 10 to 20 fold
increased risk
Transient MyeloproliferativeTransient Myeloproliferative
SyndromeSyndrome

59. Other Trisomies
 Trisomy 18 – Edward’s syndrome
 Trisomy 13 – PATAU syndrome
 High mortality

60. Edward’s
Syndrome
Trisomy 18

61. Edward’s syndrome
 1:10,000 live births
 Almost every organ system is affected
 do not live more than a few months

62. Trisomy 18 --- Edward’s
syndrome

63. Trisomy 18
Edward’s
syndrome

64. Trisomy 18
Edward’s
syndrome
Over lapping fingers & toes and
rocker bottom feet

65. Trisomy 18
Edward’s
syndrome
1.Over lapping fingers & toes
2.Rocker bottom feet
3.Syndactyly

66. Clenched fist
Trisomy 18
Edward’s
syndrome

67. Patau’s Syndrome
Trisomy-13

68. Patau’s syndrome
 1:5000 live births
 Cleft palate
 Serious eye, brain, CVS defects
 Children rarely live more than a few
months

69. Trisomy 13 --- Patau
syndrome

71. Trisomy
13

72. Trisomy
13

73. Trisomy 13 - Patau syndrome

76. When to suspect
Trisomy ?
• Congenital heart & renaldiseases
• Mental retardation
• Rocker bottom feet
• Extra digits and cleft lip / palate

77. CYTOGENETIC DISORDERSCYTOGENETIC DISORDERS
INVOLVINGINVOLVING
SEX CHROMOSOMESSEX CHROMOSOMES

78. Klinefelter’s
Syndrome

79. Klinefelter’s Syndrome

80. Klinefelter’sKlinefelter’s
SyndromeSyndrome
 47, XXY
 Male hypogonadism
 1 in 850 live male births
 Rarely diagnosed before puberty
 Increased length between sole and pubic bone
 Small testis, small external genitalia
 Lack of secondary male features

81. Klinefelter’s Syndrome
 Gynaecomastia
 ↑ FSH , Testosterone↓
 ↓ Spermatogenesis – Male Infertility
 Testis – Atrophic tubules, Prominent
Leydig cells

82. KlinefelterKlinefelter
’s’s
SyndromeSyndrome

84. KlinefelterKlinefelter
’s’s
SyndromeSyndrome

85. Klinefelter’s SyndromeKlinefelter’s Syndrome

87. Klinefelter’s SyndromeKlinefelter’s Syndrome

88. Klinefelter’s SyndromeKlinefelter’s Syndrome

89. Klinefelter’s SyndromeKlinefelter’s Syndrome

91. KlinefelterKlinefelter
’s’s
SyndromeSyndrome
Chromosomes
In sperms:
X (green)
Y (red) &
18 (orange)
Human Reproduction Vol15. no2. pp 440-444, 2000

92. Turner’s Syndrome

93. Turner’s Syndrome

94. Turner’s Syndrome
 45, X0 (57%)
 45, X0 / 46, XX – Mosaic Type
 Most common sex chromosomal
abnormality in female
 Female hypogonadism
 Infancy
 Edema of hand & foot
 Swelling of nape of neck
 CHD – Coarctation of aorta, bicuspid aortic
valve

95. Turner’s Syndrome
 1:5000 live births
 The only viable monosomy in humans
 Genetically female
 They do not mature sexually during
puberty and are sterile
 Short stature and normal intelligence
 98% of these fetuses die before birth

97. Turner’s Syndrome
 Puberty
 Failure of secondary sexual character –
Breast, external genitalia
 Short stature
 Amenorrhea – single most important
cause
 Hypothyroidism, glucose intolerance,
obesity, insulin resistance
 Atrophic ovaries

98. Turner’s Syndrome

99. Turner’s Syndrome

100. Turner’s Syndrome

101. Turner’s Syndrome

102. Turner’s Syndrome

104. Turner’s Syndrome

105. Sex chromosomal disorder
 Lyon hypothesis: Random inactivation
of one of X ch. in females.
 Inactive X ch.- Barr body / Drumstick
appendages
 Minimum of 30% cells should show
sex chromatin

106. Sex chromatin

107. Nucleus of a female
amniotic fluid cell
Top: Both X-
chromosome
territories are
detected by FISH.
Bottom: Same
nucleus stained
with Dapi.
The Barr body is
indicated by the
arrow, it identifies
the inactive X (Xi).

108. END