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Cellular and Molecular pathology > 3. Genetics and disease 2 - Monogenic disorders > Flashcards

3. Genetics and disease 2 - Monogenic disorders Flashcards

1
Q

what are monogenic disorders?

A

disorders caused by defects in a single gene
this makes them reasonably straightforward to study

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2
Q

what types of mutations result in monogenic disorders?

A

loss of function mutations like in Hirschsprung disease

gain of function mutations like in cancers (multiple endocrine neoplasia)

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3
Q

what do monogenic disorders follow?

A

simple Mendelian inheritance so it is quite easy to identify the genotype based on the phenotype

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4
Q

what is penetrance?

A

the proportion of the population with a particular genotype presents the phenotype in individuals in a population

100% penetrance = everyone with the genotype has the disease

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5
Q

what is complete penetrance?

A

100% of a genotype show the associated trait

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6
Q

what is imcomplete penetrance?

A

<100% of a genotype show the associated trait

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7
Q

why might a genotype not show the phenotype?

A

due to environmental influences

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8
Q

what is an example of incomplete penetrance?

A

BRCA1/2 genes
you can have the gene without getting the cancer

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9
Q

what is an autosomal dominant disorder?

A
  1. the dominant allele has the mutation
  2. only 1 allele needs to be affected to show the phenotype
  3. both sexes are affected
  4. they are often traceable through many generations
  5. affects heterozygous individuals for the abnormal allele
  6. 50% of offsring affected
  7. usually gain of function mutations
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10
Q

what are examples of autosomal dominant disorders?

A

huntingtions disease
hereditary rentinobastoma
achondroplasia

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11
Q

what can make identifying autosomal dominant disorders harder?

A
  1. Pleiotropy
  2. reduced penetrance
  3. variable expressivity
  4. new mutations
  5. co-dominance
  6. homozgosity
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12
Q

what is pleiotropy?

A

a single gene defect causes multiple disease phenotypes that appear unrelated but they are

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13
Q

what is reduced penetrance?

A

when there are no clinical features despite carrying a mutation

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14
Q

what is variable expressivity?

A

the range of variation in the clinical presenting phenotype in affected individuals

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15
Q

what are new mutations?

A

cases with no family history of the disorder
De novo mutations

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16
Q

what is co-dominance?

A

2 allelic traits that are both expressed in heterozygous individuals like AB blood groups

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17
Q

what is homozygosity?

A

individuals with both alleles the dominant mutation
rare but gives a more severe phenotype

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18
Q

what are autosomal recessive disorders?

A
  1. the recessive allele has the mutation
  2. affects both sexes
  3. often skips generations due to recessive nature
  4. affected individuals are homozygous for the abnormal allele
  5. Usually loss of function mutations
  6. the offspring of 2 carriers will be
    - 25% affected
    - 25% unaffected
    - 50% carriers
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19
Q

what can make identifying autosomal recessive disorders harder?

A
  1. Consanguinity
  2. psuedodominance
  3. locus heterogeneity
  4. alleic heterogeneity
  5. heterozygote advantage
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20
Q

what is consanguinity?

A

having related ancestors/parents
common in inbred communities
pick up lots of mutations that cannot be disguised by injection of new alleles

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21
Q

what is psuedodominance?

A

inheritance of a recessive trait mimics dominant inheritance usually due to loss or mutation of the dominant allele

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22
Q

what is locus heterogeneity?

A

the presnce of multiple different genetic loci that cause the same/similar phenotype
different defects cause the same result and same disease

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23
Q

what is allelic heterogeneity?

A

different alleles at one gene locus that can cause the same phenotype.
the affected individual can carry 2 different alleles and express disease = compound heterozygotes

example
different mutations in the same proteins cause the same disease

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24
Q

what is a compound heterozygote ?

A

an individual carries two different mutations at a particular gene, one on each chromosome, together they cause an autosomal recessive trait

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25
Q

what is heterozygote advantage?

A

the carriers have a survival advantage so the genotype is enriched in the population
like sickle cell disease and malaria

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26
Q

what are X-linked recessive disorders?

A
  1. mutant allele is on a X chromosome
  2. often traceable through generations
  3. affected males are hemizygous for the abnormal allele
  4. loss of function mutations
  5. offspring of a female carrier
    - 50% sons affected
    - 50% daughter carriers
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27
Q

what are examples of X- linked recessive disorders?

A

duchenne muscular dystrophy
haemophillia A and B

28
Q

why does variable expression in heterozygous females make X-linked disorders harder to study?

A

the 2nd X undergoes random gene silencing to prevent over expression
this gives a mosaic phenotype

29
Q

what causes of affected females with X-linked disorders harder to study?

A
  1. homozygosity for an X linked recessive disorder
  2. skewed X- inactivation that is not random and driven by gene expression
  3. numerical X chromosome abnormalities like XO which means the phenotype is expressed
  4. X-autosome translocations
  5. Translocations within the X
30
Q

what are X-linked dominant disorders?

A

affect hemizygous males and heterozygous females
excess of affects females in families

31
Q

what is Y linked inheritance?

A

hairy ears?
any disorder to do with spermatogenesis

32
Q

what is Partial sex linkage?

A

when psuedoautosomal X genes escape X inactivation

33
Q

what is sex influence disorders?

A

hormonal effects like male pattern baldness
virillisation in females with congenital adrenal hyperplasia

34
Q

what are pseudoautosomal genes?

A
  1. they exist in the psuedoautosomal regions of the X and Y chromosomes
  2. these regions recombine during meiosis
    3a. Partially sex-linked loci are on both sex chromosomes so they are diploid
    3b. they follow autosomal patterns of inheritance but males pass on X to daughters and Y to sons
  3. they escape X in activation
35
Q

what is the Hardy- Weinberg principle?

A

both allele and genotype frequencies in a population remain constant from generation to generation unless specific disturbing influences are introduced

it is an ideal state that provides a baseline against which change can be analysed

36
Q

what are some things that disturb the ideal state in the hardy-weinberg principle?

A

non random mating
inbreding
mutations
selection
random genetic drift
gene flow

37
Q

what is genetic flow?

A

a new influx of genes to the population

38
Q

allele frequency

A

allele A = frequency p
allele a = frequency q
p+q=1 (100%)

39
Q

genotype frequency

A

AA = p^2
aa = q^2
Aa = 2pq

p^2 +2pq+q^2 = 1 (100%)

40
Q

what is cystic fibrosis?

A
  1. autosomal recessive
  2. CFTR gene that encodes cystic fibrosis transmembrane regulator
  3. incidence 1/2000 carriers 1/22
  4. defective secretory systems part of innate immunity
  5. thick mucus, trapped bacteria, chronic lung disease, pancreatic failure, premature death
  6. Symptom severity can depend on the mutation of the combo of mutations
41
Q

CFTR genetic info

A

250KB
27 exons
6.5Kb mRNA
1480 aa protein

42
Q

cystic fibrosis transmembrane regulator protein function

A

mucosal transmemrbane protein
chlroide channel with ATP binding site
Cl- leaves the cell and water follows which helps with secretions

43
Q

CFTR mutations

A

F508 = phenylalanine deletion that causes a protein folding defect, leading to degradation and reduce surface expression
>60 other mutation sites

44
Q

CFTR advantage

A

thought to be protective against S. Typhi as it uses the protein to enter the cells

45
Q

what is duchenne muscular dystrophy (DMD)?

A
  1. X-linked recessive
  2. DMD gene
  3. encodes dystrophin
  4. Incidence = 1/4000
  5. usually causes death before 30
  6. affects girl with translocation through Xp21
  7. affects boys with other abnormalities in Xp21
46
Q

DMD gene

A

2000Kb
>65 exons
16Kb mRNA
3685 amino acid protein

47
Q

DMD protein Function

A

427kD
common features with muscle structural proteins
links actin to a protein complex in the plasma membrane

48
Q

DMD mutations

A

large deletions = absent/truncated protein = severe disease
small deletions = partly truncated protein = mild disease

49
Q

what is Huntingtons disease?

A
  1. autosomal dominant
  2. HTT gene
  3. protein huntingtin
  4. very rare = incidence 1/37000
  5. all cases in the US can be traced back to 2 brothers
  6. progressive neurological condition with loss of coordination
  7. late onset
50
Q

HTT gene

A

one of the first maped by linkage
180kb
67exons
13.7kb mRNA
(CAG)n repeats

51
Q

HTT protein - huntingtin

A

normally 348kD
no known homology with other proteins
more repeats in disease protein

52
Q

HTT mutation

A
  1. a trinucleotide repeat CAG that is normally present 16-36 times
  2. disease sufferes have 42-86 repeats
  3. the number of repeats increases through the generations
  4. more repeats = more severe symptoms
  5. called dynamic mutations
53
Q

trinucleotide repeat disorders

A
  1. all have (XYZ)n
  2. n is increased in affected individuals
  3. result of founder effect mutations
  4. often severity of symptoms increase through generations
54
Q

what are the classes of trinucleotide repeat disorders?

A
  1. fragile site
  2. neurodegenerative
  3. myotonic dystrophy
  4. friedrich ataxia
55
Q

Fragile site diseases

A

All chromosomes have fragile sites where they are more likely to break at this point under cellular stress

Repeat expansion can increase the size of these fragile sites and make breakage more likely
eg fragile X

56
Q

neurodegenerative trinucleotide repeat disorders

A

(CAG)n with n<150
multiple effects on protein protein interactions and cause toxic protein aggregates

57
Q

myotonic dystrophy: trinucleotide repeat disorder

A

(CTG)n with n= 200-400
in the 3’ untranslated region which effects the mRNA
progressive muscle weakness and prolonged muscle contraction - myotonia

58
Q

trinucleotide repeat disorder: Friedrich ataxia

A

(GAA)n with n =200-900
within the intron which decreases transcription
progressive damage to the nervous system

59
Q

what are haemoglobinopathies?

A

inherited disorders of haemoglobin structure or synthesis
includes sickle cell aneamia and thalassaemia

60
Q

how does haemoglobin expression change throughout your life?

A
  1. variable expression with different affinities
  2. foetal Hb have higher affinity to get oxygen from the mother. this stops being expressed around 40 weeks old
  3. adult Hb can be HbA or HbA2
  4. HbA2 is expressed in low levels in every RBC but we dont really know what it does but it appears to have a higher affinity then HbA
61
Q

what is sickle cell disease?

A
  1. autosomal recessive
  2. common in endemic malaria areas
  3. 1/100 incidence
  4. ß-globin defect
    - GAG to GTG
    - Glu - Val
    HbB to HbS
  5. HbS is hydrophobic so forms the sickle shapes and is quite brittle causing the destruction of RBC causing anaemia
62
Q

what can causes changes in the haemoglobin structure?

A
  1. point mutations
  2. deletions and insertions
  3. frameshifts
  4. chain termination
  5. fusion chain
63
Q

how does the rare Hb lepore occur?

A

Misaligned crossing over in meiosis creating a fusion Hb protein
- usualy fine but if you have compound heterozygous with another mutation is causes disease

64
Q

what are the thalassaemias?

A
  1. disorders in the synthesis of haemoglobin
  2. autosomal recessive
65
Q

ß-thalassaemia

A
  1. lack of ß global chains
  2. not normally caused by gene deletions but point mutations insertions and deletions
  3. causes free a chains which precipitate and destroy RBC precursor
  4. OR causes continued production of y globin which release oxygen less readily causing bone deformity and wasting disease
66
Q

alpha-thalassaemia

A
  1. deletion of a chain gene
  2. a1 +a2 deleted = severe disease
  3. a1 or a2 deleted = mild disease
  4. if all 4 gene deleted then death
  5. 3 genes deleted = variable anaemia
  6. 1 or 2 genes deleted = mild anaemia
67
Q

deltaß-thalassaemias

A
  1. reduced synthesis of both delta and ß chains
  2. rare
  3. mild to severe anaemia
  4. mild form = hereditary persistance of foetal haemoglobin affecting oxygen delivery

Cellular and Molecular pathology (25 decks)

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