3. Genetics and disease 2 - Monogenic disorders

Question 1

what are monogenic disorders?

Answer 1

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

Question 2

what types of mutations result in monogenic disorders?

Answer 2

loss of function mutations like in Hirschsprung disease

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

Question 3

what do monogenic disorders follow?

Answer 3

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

Question 4

what is penetrance?

Answer 4

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

Question 5

what is complete penetrance?

Answer 5

100% of a genotype show the associated trait

Question 6

what is imcomplete penetrance?

Answer 6

<100% of a genotype show the associated trait

Question 7

why might a genotype not show the phenotype?

Answer 7

due to environmental influences

Question 8

what is an example of incomplete penetrance?

Answer 8

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

Question 9

what is an autosomal dominant disorder?

Answer 9

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

Question 10

what are examples of autosomal dominant disorders?

Answer 10

huntingtions disease
hereditary rentinobastoma
achondroplasia

Question 11

what can make identifying autosomal dominant disorders harder?

Answer 11

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

Question 12

what is pleiotropy?

Answer 12

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

Question 13

what is reduced penetrance?

Answer 13

when there are no clinical features despite carrying a mutation

Question 14

what is variable expressivity?

Answer 14

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

Question 15

what are new mutations?

Answer 15

cases with no family history of the disorder
De novo mutations

Question 16

what is co-dominance?

Answer 16

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

Question 17

what is homozygosity?

Answer 17

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

Question 18

what are autosomal recessive disorders?

Answer 18

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

Question 19

what can make identifying autosomal recessive disorders harder?

Answer 19

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

Question 20

what is consanguinity?

Answer 20

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

Question 21

what is psuedodominance?

Answer 21

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

Question 22

what is locus heterogeneity?

Answer 22

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

Question 23

what is allelic heterogeneity?

Answer 23

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

Question 24

what is a compound heterozygote ?

Answer 24

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

Question 25

what is heterozygote advantage?

Answer 25

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

Question 26

what are X-linked recessive disorders?

Answer 26

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

Question 27

what are examples of X- linked recessive disorders?

Answer 27

duchenne muscular dystrophy haemophillia A and B

Question 28

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

Answer 28

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

Question 29

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

Answer 29

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

Question 30

what are X-linked dominant disorders?

Answer 30

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

Question 31

what is Y linked inheritance?

Answer 31

hairy ears? any disorder to do with spermatogenesis

Question 32

what is Partial sex linkage?

Answer 32

when psuedoautosomal X genes escape X inactivation

Question 33

what is sex influence disorders?

Answer 33

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

Question 34

what are pseudoautosomal genes?

Answer 34

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 4. they escape X in activation

Question 35

what is the Hardy- Weinberg principle?

Answer 35

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

Question 36

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

Answer 36

non random mating inbreding mutations selection random genetic drift gene flow

Question 37

what is genetic flow?

Answer 37

a new influx of genes to the population

Question 38

allele frequency

Answer 38

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

Question 39

genotype frequency

Answer 39

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

Question 40

what is cystic fibrosis?

Answer 40

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

Question 41

CFTR genetic info

Answer 41

250KB 27 exons 6.5Kb mRNA 1480 aa protein

Question 42

cystic fibrosis transmembrane regulator protein function

Answer 42

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

Question 43

CFTR mutations

Answer 43

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

Question 44

CFTR advantage

Answer 44

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

Question 45

what is duchenne muscular dystrophy (DMD)?

Answer 45

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

Question 46

DMD gene

Answer 46

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

Question 47

DMD protein Function

Answer 47

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

Question 48

DMD mutations

Answer 48

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

Question 49

what is Huntingtons disease?

Answer 49

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

Question 50

HTT gene

Answer 50

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

Question 51

HTT protein - huntingtin

Answer 51

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

Question 52

HTT mutation

Answer 52

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

Question 53

trinucleotide repeat disorders

Answer 53

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

Question 54

what are the classes of trinucleotide repeat disorders?

Answer 54

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

Question 55

Fragile site diseases

Answer 55

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

Question 56

neurodegenerative trinucleotide repeat disorders

Answer 56

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

Question 57

myotonic dystrophy: trinucleotide repeat disorder

Answer 57

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

Question 58

trinucleotide repeat disorder: Friedrich ataxia

Answer 58

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

Question 59

what are haemoglobinopathies?

Answer 59

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

Question 60

how does haemoglobin expression change throughout your life?

Answer 60

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

Question 61

what is sickle cell disease?

Answer 61

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

Question 62

what can causes changes in the haemoglobin structure?

Answer 62

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

Question 63

how does the rare Hb lepore occur?

Answer 63

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

Question 64

what are the thalassaemias?

Answer 64

1. disorders in the synthesis of haemoglobin 2. autosomal recessive

Question 65

ß-thalassaemia

Answer 65

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

Question 66

alpha-thalassaemia

Answer 66

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

Question 67

deltaß-thalassaemias

Answer 67

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