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Pathology MBBS > Genetics > Flashcards

Genetics Flashcards

1
Q

Classification of genetic diseases

A 
1. Single gene disorders:
 Mendelian: (4 types)
 Non Mendelian:
  Germ line mosaicism
  Trinucleotide repeat mutation
  Genomic imprinting
  Mitochondrial inheritance
2. Chromosomal disorders:
 Structural and Numerical
3. Multifactorial
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2
Q

Sperm mitochondrial DNA is eliminated. How

A

Ova eliminates all sperm mitochondrial DNA by ubiquitin proteasome pathway

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3
Q

The organs usually affected by mitochondrial inheritance are

A

Brain
Skeletal muscle
Eye, as they contain more amounts of mitochondria

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4
Q

Heteroplasmy

A

Presence of normal and mutant mitochondrial DNA in the same person

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5
Q

Examples of diseases of mitochondrial inheritance

A 
K. Kearns Sayre syndrome
L. Leigh syndrome,
 Leber Hereditary optic neuropathy
M. MELAS
N. NARP syndrome
O. CPEO
P. Pearson syndrome
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6
Q

Most common disease inherited through mitochondrial inheritance

A

MELAS

Mitochondrial Encephalopathy
Lactic Acidosis and
Stroke like episodes

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7
Q

Most common mitochondrial myopathy

A

CPEO
Chronic Progressive
External Ophthalmoplegia

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8
Q

Diseases due to trinucleotide repeat mutations in the coding region

A

Huntington’s disease CAG

Spinocerebellar ataxia CAG

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9
Q

Diseases due to trinucleotide repeat mutations in the non coding region

A

Fragile X syndrome CGG
Friedreich’s ataxia GAA
Myotonic dystrophy CTG

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10
Q

Cause of fragile X syndrome

A 
Mutation in FMR1 gene
➡️ increased CGG repeats 
5-40 CGG- normal
55-200 repeats- premutation
200-4000 repeats- full mutation
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11
Q

Anticipation/ Sherman’s paradox

A

CGG repeats increases with each generation

Increased CGG repeats causes fragile X syndrome

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12
Q

Why is fragile X syndrome called the way it is

A

When cells are cultured in a folate deficient media, constriction is seen in the X chromosome as if the X chromosome is broken

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13
Q

Clinical presentation of fragile X syndrome

A
  1. 2nd most common genetic cause of mental retardation
  2. Large head, everted ears, mandible
  3. Large testis/ macrorchidism- most distinctive feature
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14
Q

Fragile X tremor syndrome

A

Gene affected- FMR1
Gain of function mutation ➡️ intentional tremor
(Opposite effect of fragile X syndrome)

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15
Q

Gonadal mosaicism

A

Type of autosomal dominant disorder
Even if both parents are normal, child may be affected
Post zygotic mutation ➡️ mutation only in gametes, not in somatic cells

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16
Q

Examples of gonadal mosaicism

A

Tuberous sclerosis

Osteogenesis imperfecta

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17
Q

Genomic imprinting

A

Gene silencing/ inactivation
Either paternal/ maternal allele is inactivated ➡️ only one allele is functional
Normal phenomenon
Due to epigenetics

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18
Q

Epigenetics

A

Heritable modifications in DNA/ histone like DNA methylation or histone deacetylation ➡️ loss of expression of genes

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19
Q

Prader Willi syndrome

Cause

A

Maternal allele of chromosome 15q is usually silent, then
Paternal deletion: cause
Loss of function of SNORP gene

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20
Q

Features of Prader Willi syndrome

A 
Short stature
Hypotonia
Hypogonadism
Hyperphagy (increased ghrelin)➡️ obesity
Mental retardation
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21
Q

Causes of Angelman syndrome/ Happy Puppet syndrome

A

Paternal allele was silenced
The functional maternal is deleted then Angelman syndrome
Defect in ubiquitin ligase gene (UBE3A)

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22
Q

Features of Happy Puppet syndrome/ Angelman syndrome

A 
Inappropriate laughter
Ataxia
Seizures
Mental retardation
Hypotonia
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23
Q

Uniparental disomy

A

If both alleles come from same parent
Prader Willi syndrome: paternal deletion/ maternal disomy
Angelman syndrome: the opp

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24
Q

Autosomal dominant disorder characteristics

A

Usually have adult onset
Does not skip generations
Usually due to structural protein defects
1. Incomplete penetrance
2. Variable expressivity
Most common Mendelian mode of inheritance

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25
Q

Examples of autosomal dominant disorders

A 
He has a very dominant father
H. Huntington’s disease
H. Hereditary spherocytosis 
A. APKD
V. VWF, VHL
D. Dystrophia myotonica
O. Osteogenesis imperfecta
M. Marfan’s syndrome
I. Intermittent porphyria
N. NF-1
A. Achondroplasia
N. NF-2
T. Tuberous sclerosis
F. FAP, Familial hypercholesterolemia
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26
Q

Marfan’s syndrome

Cause

A

Autosomal dominant
Defect in FBN-1 gene encoding for fibrillin-1
(defect in FBN-2 gene encoding for fibrillin-2 leads to congenital contractural arachnodactyly)

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27
Q

Clinical presentation of Marfan’s syndrome

A 
1. Skeletal defect:
 Tall stature 
 Hyperextensible joints
 Dolicocephalic head 
2. Ocular defects:
 Ectopia lentis 
 Superotemporal dislocation
3. CVS:
 MV Prolapse (like Klinefelter’s)
 Aortic dissection
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28
Q

Most common cause of death in Marfan’s syndrome

A

CVS defect like aortic dissection

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29
Q

Diagnosis of Marfan’s syndrome

A

Revised Ghent’s criteria

  1. Family history
  2. Clinical signs and symptoms
  3. Fibrillin-1 gene mutation
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30
Q

NF-1 or von Recklinghausen’s disease

A

Gene on chromosome 17 (letters)
Encode for neurofibromin
Can be associated with juvenile myelo monocytic leukaemia (JMML)
Presentations:
1. Cafe au lait spots (>6 spots)
2. Lisch nodules: (pigmented iris hamartomas)
3. Neurofibromas: (meningeomas, pheochromocytoma)

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31
Q

NF-2

A

Gene on chromosome-22
Encodes for Merlin
Associated with bilateral acoustic neuroma/ Schwannomas)

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32
Q

Ehler Danlos syndrome basics

A 
AD and AR (type 6,7)
Type 3 collagen mostly affected
Most common : 3
Least common: 7
Most dangerous type of EDS:
 Type 4 (vascular)
33
Q

AD types of Ehler Danlos syndrome

A 
1. Classical:
 Diaphragmatic hernia
 Mitral valve prolapse
3. Common, hypermotility:
 Loose skin (Rubberman syndrome)
 Thin skin (cigarette paper skin)
4. Vascular:
 Aorta may rupture
34
Q

AR types of Ehler Danlos syndrome

A 
6. Kyphoscoliosis
Defect in lysyl hydroxylase enzyme
7. 
 a,b: arthrochalasia:
  Joint, bone defects
 c: Dermatosparaxis:
  Severe skin fragility
35
Q

Autosomal recessive disorders

A

Young/ early onset usually
Complete penetrance
Usually due to enzyme deficiency
Uniparental disomy (both alleles from a single parent) can also be seen

36
Q

Examples of autosomal recessive disorders

A 
A. Alkeptonuria, Ataxia, Albinism
B. Beta thalassemia, sickle cell anaemia
C. Cystic fibrosis, congenital adrenal hyperplasia
D. Deafness
E. Emphysema (α1 antitrypsin deficiency)
F. Friedrich’s ataxia
G. GSDs, Galactosemia 
H. Hemachromatosis, homocystinuria
I. Inborn error of metabolism
37
Q

All lysosomal storage disorders are autosomal dominant except

A

Fabry’s disease
Hunter’s disease
Autosomal recessive

38
Q

Tay Sachs disease mnemonic

A 
T. Tay Sachs
A. Ashkenazi Jews 
Y. Young
S. Spot- cherry red in macula
A. AR
C. CNS defects
H. Hexosaminidase α defect (GM2 increases)
S. Symptoms of motor neuron and mental retardation
39
Q

Histopathology of Tay Sachs disease

A 
Neuron:
 Ballooned
 Vacuolation (distended with lysosomes)
Electron microscopy:
 Onion skin appearance
40
Q

Onion skin appearance

A 
X-ray: Ewing’s sarcoma 
e- microscopy: Tay Sachs disease 
Nerve biopsy: CIPD
H and E: malignant hypertension, 1° sclerosing cholangitis
Gross: spleen in SLE
41
Q

Niemann Pick’s disease

Types

A 
Defect in sphingomyelinase  ➡️ accumulation of sphingomyelin
Type A: Neuronal involvement
 Severe, early mortality
Type B: Neuronal involvement absent
 Better prognosis
Type C: most common, intermediate
42
Q

Gaucher’s cell

A

Wrinkled/ crumpled tissue paper appearance
PAS +
Oil red O+
Perl’s +

43
Q

Pseudo Gaucher’s cell

A

Seen in CML

Perl’s stain -ve

44
Q

Types of Gaucher’s disease

A 
1. Non neuropathic:
 Adulthood
 Most common
 Bone involvement, pathological fractures
 Hepatosplenomegaly
2. Neuropathic:
 Infants
 Less common
 More severe
 CNS involvement
3. Intermediate
45
Q

X-linked recessive disease examples

A 
Lady. Lesch Nyhan syndrome
Hardinge. Haemophilia A and B, Hunter’s disease
College. Colour blindness
Girls. G6PD deficiency
Don’t. Duchenne muscular dystrophy
Care. Chronic granulomatous disease
About. Agammaglobulinemia
Foolish. Fabry’s disease, Fragile X syndrome
Words. Wiscott Aldrich syndrome
46
Q

X-linked dominant disorders example

A

R. Rett’s syndrome
A. Alport syndrome
V. Vit D resistant rickets
I. Incontinentia pigmenti

47
Q

X-linked dominant properties

A

Mother: can give diseases to both sons and daughters
Father: affects only daughters

48
Q

Types of chromosomes

A 
Metacentric: 1
Submetacentric: X
Acrocentric:
 13,14,15,,21,22,23Y
Telocentric: does not exist in humans
49
Q

Chromosomal disorders

A 
1. Structural:
 Deletion
 Insertion
 Translocation
 Ring chromosome
 Iso chromosome
 Inversion
2. Numerical:
 Aneuploidy; monosomy and trisomy
50
Q

Reasons for aneuploidy

A
  1. Meiotic non dysjunction

2. Anaphase lag

51
Q

Ring chromosome

A

Type of structural chromosomal abnormality
Break at both ends
Fusion of damaged ends
Can be seen in Turner’s syndrome

52
Q

Robertsonian translocation

A

Translocation between 2 acrocentric chromosomes (13,14,15,21,22,Y)
t(14:21) Down’s syndrome

53
Q

Isochromosome

A

When division of chromosome occurs transversely instead of longitudinally
Two short or two long arms
Most common isochromosome: iXq

54
Q

Most common isochromosome in:
Cancer
Testicular tumour

A

In cancer: il7q

In testicular tumour: i21p

55
Q

Down’s syndrome pathogenesis

A 
Most common chromosomal disorder
Most common genetic cause of mental retardation
1. Meiotic non dysjunction:
 95%
 Occurs in oogenesis in meiosis-I
2. Robertsonian translocation:
 4%
 t(14:21)
3. Mosaics: 1%
56
Q

Down’s syndrome screening tests for mothers

A 
Triple test:
 AFP
 βBCG
 Unconjugated estradiol
Quadruple test:
 Triple test + inhibin
57
Q

Clinical features of Down’s syndrome

A
  1. Most common cause of mental retardation
  2. Face: mongoloid idiocy
  3. Eyes: Brush field spots
  4. Palm: (single) Simian crease, clinodactyly
  5. Foot: Sandle gap/ saddle toe
58
Q

Mongoloid idiocy

A

Facial features of Down’s syndrome

  1. Flat facial profile
  2. Upslanting/ oblique palpebral fissure
  3. Prominent epicanthal folds
  4. Flat occiput
  5. Flat nasal bridge
  6. Low set ears
59
Q

Complications of Down’s syndrome

A
  1. Acute leukaemia
  2. Cardiovascular defect:
    M/C endocardial cushion defect, VSD
  3. GIT:
    Annular pancreas
    Duodenal atresia
    Hirschsprung disease
  4. Hypothyroidism
  5. Premature Alzheimer’s disease (gene for the disease on chromosome 21)
60
Q

Acute leukaemia and Down’s syndrome

A

M/C leukaemia- ALL
M/C in children <3 years- AML
M/C type of AML- AML M7

61
Q

Common features of Patau’s syndrome and Edward’s syndrome

A
  1. Mental retardation
  2. CVS defect
  3. Rocker bottom feet
  4. Prominent occiput
62
Q

Patau syndrome specific characteristics

A 
Microcephaly 
Micro ophthalmia
Umbilical hernia
Polydactyly
Left lip and palate

Meiotic non dysjunction occurs in meiosis-I
13 chromosome trisomy

63
Q

Edward’s syndrome specific characteristics

A 
Micrognathia
Short neck
Renal malformation
Limited hip abduction
Overlapping fingers

Meiotic non dysjunction occurs in meiosis-II (unlike others)
18 chromosome trisomy

64
Q

Cat eye syndrome

A

Trisomy 22

Multiple colobomas in the eye

65
Q

Cat cry syndrome or Cri du chat syndrome

A

del 5p (short arm)
Cat-like cry
Behavioural abnormalities
Developmental delay

66
Q

Lyon’s hypothesis

A

Only one X chromosome of genetically active
Other X, paternal or maternal, randomly becomes inactivated
Inactivated X chromosome- Barr body of buccal mucosa having drumstick appearance
(21 % of Xp and 3% of Xq escape inactivation)

67
Q

Syndromes associated with advanced maternal age

A

Down’s syndrome

XXX syndrome

68
Q

Syndromes associated with advanced paternal age

A

Marfan’s syndrome
Osteogenesis imperfecta
Achondroplasia

69
Q

Klinefelter’s syndrome

A

Associated with both advanced maternal and paternal age
Expected hormonal changes
M/C cause of male hypogonadism
M/C cancer: breast cancer
M/C germ cell tumour: extragonadal GCT (teratoma)

70
Q

Biopsy test for Klinefelter’s syndrome

A

Atrophy of seminiferous lobules
Hyalinisation of lobules
Leydig cell hyperplasia

71
Q

Features of Klinefelter’s syndrome

A
  1. Tall stature
  2. Eunuchoid body habitus
  3. Long extremities
  4. Reduced 2° sexual characteristics
  5. Gynecomastia
  6. Frontal baldness absent
  7. Poor muscle tone
  8. Testicular atrophy- infertility
72
Q

Turner’s syndrome basics

A

Most common female hypogonadism
Only monosomy compatible with life
Most common cause of primary amenorrhea
M/C monosomy- monosomy 16

73
Q

Pathology of Turner’s syndrome

A
  1. Deletion of X chromosome
  2. Ring chromosome
  3. ISO chromosome
74
Q

Common features of Turner’s syndrome

Mneumonic

A

C. Cardiac abnormalities, cubitis valgus, cystic hygroma
L. Lymphadema
O. streaked ovaries
W. Webbed neck
N. Normal intelligence, nipples widely spaced
S. Short stature, short 4th metacarpal

75
Q

CVS abnormalities of Turner’s syndrome

A

M/C CVS defect: bicuspid aortic valve
M/C cause of death: preductal coarctation of aorta
M/C cause of 1° amenorrhea
Increased risk of developing gonadoblastoma

76
Q

Noonan’s syndrome

A

Clinical features of Turner’s syndrome
Normal karyotype
Mutation in chromosome 12

77
Q

Karyogram

A

Arrangement of chromosomes in descending order of length followed by sex chromosomes

78
Q

Samples used for karyotyping

A
  1. Amniotic fluid
  2. Chorionic villi sampling
  3. Skin fibroblasts
  4. Peripheral blood lymphocytes

Arrested the cell in metaphase using colchicine

79
Q

Staining/ banding for karyotyping

A
  1. Mc giemsa banding

2. Q- banding (quinalrine)

Pathology MBBS (17 decks)

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