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GGE > Genetics 9 - Cystic Fibrosis and Genetic Screening > Flashcards

Genetics 9 - Cystic Fibrosis and Genetic Screening Flashcards

1
Q

learning outcomes

A
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2
Q

why do some communities/ethnic groups have different risk of inherited genetic disorders than the general population

A

founder effect

reduction in genetic variation due to migration/isolation of a small number of endogamous individuals from a large population

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3
Q

endogamy

A

marriage within a specific community

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4
Q

syndrome associated with Pennsylvania Amish

A

Eilis van Creveld syndrome

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5
Q

symptoms of Eilis van Creveld syndrome

A

short stature

polydactyly

abnormality of nails and dentition

cardiac defects

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6
Q

allele frequency of Eilis van Creveld in Pennsylvania Amish and in General Northern European population

A

7% - Amish

0.1% - Northern European population

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7
Q

gene associated with Eilish van Creveld syndrome

A

EVC gene short arm of chr 4

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8
Q

requirements for founder effect

A

relatively discreet breeding sub-population (endogamy)

derived from a small group of related people (founders)

if a specific mutation was present by chance in the founders it may be disproportionately common in the expanded group derived from that population

likewise, frequent disease associated alleles that are by chance missing in the founders may be disproportionately uncommon in the expanded group derived from that population

exogamy (marrying unrelated people) will tend to dilute or diminish founder effect

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9
Q

founder effect and genetic drift

A

genetic drift = change in allele frequency due to chance i.e. which copy of the allele you’re going to inherit

effect on larger populations is a lot smaller

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10
Q

symptoms of Fanconi Aplastic Anaemia

A

rare genetic syndrome characterised by short stature, various congenital abnormalities, bone marrow failure and cancer predisposition

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11
Q

pattern of inheritance - Fanconi Aplastic Anaemia

A

autosomal recessive

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12
Q

heterozygotes - FAA

A

may have short stature, but no bone marrow aplasia or increased cancer risk

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13
Q

genetic variants associated with FAA

A

lots but NB:

FANCA chr 16

FANCC chr 9q

FANCG chr 9p

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14
Q

what is FA pathway responsible for

cells most affected

what is their predisposition to

proportion that develop cancer

age of onset

associated diseases

A

FA pathway - fixing DNA damage during DNA replication

quick dividing cells most affected - bone marrow, foetal

predisposition to malignancies in surviving cells

about 20% homozygotes develop cancer

median age of onset = 16

haematological malignancy (AML, MDS, ALL)

squamous cell cancers

hepatomas

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15
Q

prevalence and carrier frequency of Fanconi Anaemia

A

overall prevalence - 1 in 5m

carrier freq - 1 in 200, 1 in 300

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16
Q

genetic bottleneck

A

relatively small initial population - founders

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17
Q

high incidence of what genetic diseases (Ashkenazi Jews)

A

Cystic Fibrosis

Tay-Sachs

Fanconi anaemia

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18
Q

carrier screening

A

testing a target population to identify unaffected carriers of a disease allele

done in NA for Tay-Sachs

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19
Q

homozygotes - Tay-Sachs

A

fatal

deficiency in lysosomal enzyme β-hexosaminidase A (HEX A) - substrate GM2 ganglioside accumulates

blindness, seizures, hypotonia - neuronal damage

death by 5 years

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20
Q

principles of population screening

A

each screening programme needs to be appraised for viability, effectiveness and appropriateness in each target population

condition - serious, well understood, and relatively common (cost/benefit)

test - acceptable, easy and cheap, valid and reliable

intervention - effective treatment/counselling, prenatal diagnosis and ART available

screening programme - effective (clinical data), ethical, benefit outweighs harms

implementing criteria - accessibility, resources for diagnosis and treatment, communication of results, data privacy, quality assurance

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21
Q

gene associated with CF

type of regulator

domains

function

A

CFTR gene

ion channel (Cl and HCO3-)

chr 7q31.2 (locus)

27 exons and 230,000 bps (large)

12 transmembrane domains, 2 nucleotide binding domains

1 regulatory domain

function = gating - ATP dependent cycling between conducting ions (open) and not conducting ions (closed)

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22
Q

cystic fibrosis manifestions

A

sweat (Na+ > 60 mmol/L)

lungs - thick sticky mucus, infections

GIT (may present with obstruction in infancy - meconium ileus)

frequent greasy, bulky stools (steatorrhea)

sinuses - polyps, thick sticky mucus, infections

pancreas (malabsorptionm failure to thrive, CF)

male infertility - congenital bilateral absence of vas deferens (CBAVD) - 95%

female infertility - thickened cervical mucus

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23
Q

resp mucosa - normal vs CF

A

Main differences In airway surface layer that protects airway

Reduced Cl- secretion and hyperabsorption - dehydration of layer

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24
Q

CF mutations

A

hypomorphic (less function) heterogeneity - 1000s of alleles associated with disease are known

LOF mutations tend to be more heterogeneous than GOF mutations

recessive pattern of inheritance (affected people usually have unaffected parents)

CFTR has biallelic expression - limited/no clinical effect in heterozygote as CFTR protein is haplosufficient

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25
Q

carrier rate for CF mutation in Ireland

A

1 in 19 (1 in 25 northern Europeans)

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26
Q

most common abnormal CFTR allele

A

p.F508del = ΔF508

70% of CF alleles in northern Europeans

deletion of phenylalanine at position 508 in CFTR (in nucleotide binding domain 1)

altered CFTR protein is degraded IC and does not make it to the apical cell membrane (loss of function)

FRAMESHIFT MUTATION

deletion of 3 nucleotides in exon 10

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27
Q

CF - type of mutation

A

frameshift

ΔF508

deletion of 3 nucleotides in exon 10

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28
Q

why is mutation in CFTR gene so common

A

heterozygote advantage - protected against dehydration due to diarrhea - cholera, typhoid fever epidemics

29
Q

screening available for CF

A

individuals/couples could be tested to determine if heterozygous (Aa) with a view to planning pregnancy

testing of embryos for purposes of embryo selection

prenatal testing on amniotic fluid with a view to termination of pregnancy

screening of newborns to provide early detection and intervention

the challenge is > 2000 mutations

  • IRT - immunoreactive trypsinogen
  • Blood spot test
  • CF mutational analysis plan
30
Q

things to remember

A
31
Q
A

C?

32
Q

learning outcomes

A
33
Q
A

CF

marked reduction in life expectancy

duration and wuality of life critically dependent on quality of services

repeated LRTI with progressive destruction of lung tissue - bronchiectasis and resp failure

34
Q

CF pulmonary infection - bacteria

A

different bacteria cause infection at different stages

age at which they become permanently colonised/infected with pseudomonas aeruginosa is a critical issue

bacteria comes from everywhere

35
Q

what is meconium ileus

prevalence

gene associated

A

obstruction of GIT of infant related to inspissated (thick, dehydrated) material

occurs in 15-20% of infants with CF

genotype at CF modifier 1 (CFM1) gene on chr 19 may determine risk of developing meconium ileus

36
Q

how to confirm CF if suspected

A

define the mutations - targeted mutation panel

if not a common mutation, scan exons by PCR amplification and Single Strand Conformation Polymorphism - sequence exons that look different from controls

37
Q

CF carrier - A vs a

A

A = any CFTR allele that results in a functioning chloride channel - sequence may vary

a = any CFTR allele that does not code for a functioning chloride channel

> 2000 mutated CFTR alleles that have been described

RECALL: LOF are a lot more heterogenous than GOF mutations

38
Q

LOF vs GOF

A

RECALL: LOF are a lot more heterogenous than GOF mutations

39
Q

5 mutation categories - CF

A
  1. protein production - no functional protein produced
  2. protein processing - misfolding (DF508 - doesn’t go to where it is supposed to go (surface of cell) because it has not folded correctly)
  3. gating - doesn’t open
  4. conduction - faulty channel
  5. insufficient protein - splice site (Changes in sequence - not enough protein produced - often in promoter)
40
Q

CFTR pharmacogenetics - 3 categories of therapies designed to treat faulty CFTR

A

CFTR modulator therapies are designed to correct the malfunctioning protein made by a mutated CFTR

  • read-through compounds (non-sense)
  • correctors (misfolding)
  • potentiators (open channel/increase function) - Channel openers - constitutively open, even if protein is not working properly
41
Q

gating mutation - less common

treatment

A

e.g. G551D (glycine changed to aspartic acid at position 551)

4-5% of cases of CF (depends on population)

CFTR protein is in place in cell membrane but does not work because Cl- channel does not open

Ivacaftor (Kalydeco) (potentiator) binds to CFTR and allows it to open

does not work for DF508 but combination drug Orkambi (corrector) does

42
Q

triple therapy used to treat CF

A

available for patients 12+ with at least 1 DF508 and 1 minimal function mutation

increase quantity and function of F508del-CFTR protein at cell surface

may be extended to patients under 12 in the future

43
Q

elexacaftor, tezacaftor

A

correctors

44
Q

ivacaftor

A

potentiator

45
Q

implications for family of a person with CF

A

carrier analysis may be requested - cascade screening

carrier testing available to adults > 16 where there is a family history of CF or where a family member has been found to carry a CF mutation (If they are carrier - IVF, embryo selection, gene therapy (CRISPR-Cas))

46
Q

chance of getting CF if both parents are carriers

A

25%

47
Q

purpose of genetic screening for CF

A

carrier screening - to plan pregnancy

testing of embryos - embryo selection

prenatal testing on amniotic fluid/CVS - termination of pregnancy

newborn screening - early detection and intervention

→ high energy diet, physio, medicines for lung function and gut absorption

48
Q

treatment for newborns with CF

A

high energy diet

physio

medicines for lung function and gut absorption

49
Q

Heel prick test

A
50
Q

newborn screening for CF

A

IRT screening has low specificity

relatively high false +ve rate

combined with mutational analysis vastly improves specificity

2% of carriers of CF born each year will also be detected

51
Q

why is there no CF population carrier screening

A
52
Q

how to screen adults for carriage of CF gene

A

testing just for DF508 is straightforward

amplify relevant sequence from genomic DNA

assess for wt or DF508 sequence (restriction enzyme/oligonucleotide probe)

assess for DF508 during amplification using real time approach

other common mutations - 38 mutation panel detects 93.5% of the CF mutations found in Irish population

53
Q

NGS and CF

A

affordable genetic testing based on the identification of variants in extended genomic regions - 99% detection rate

also being used to design custom CFTR mutation panels for different geographic regions - 95% detection rate

54
Q

screening for carriage depends on

A

ethnic background

55
Q

why is DF508 not the predominant mutation across the globe

A

founder effect

56
Q

Haemochromatosis

A

accumulation of iron - liver, skin and other tissues

manifestations develop in adult life - age of onset is variable

hepatic and cardiac failure

skin pigmentation

joint disease

common

57
Q

diagnosis of haemochromatosis

A

elevated transferrin saturation

elevated serum ferritin levels

58
Q

haemochromatosis treatment

A

phlebotomy

59
Q

with whom is haemochromatosis more common and why

A

More common in men than women due to menstruation

60
Q

gene - haemochromatosis

pattern of inheritance

A

variants alleles of the HFE gene 6p21.3

autosomal recessive

HFE regulates iron absorption from the diet and iron storage

deficiency = iron overload

61
Q

2 key mutations - haemochromatosis

A
  1. G to A transition at nucleotide 845 (c.845G>A) - cysteine to tyrosine (p.C282Y)
  2. C to G at nucleotide 187 (c.187C>G) - histidine to aspartic acid 63 (p.H63D)
62
Q

most common mutations

A

C282Y homozygous in 80-85% haemochromatosis cases (3x increase Fe absorption)

also C282Y and H63D compound heterozygotes

homozygous H63D does not result in clinically manifested haemochromatosis

63
Q

penetrance of haemochromatosis

A

as low as 1%

64
Q

is haemochromatosis a hereditsry disease

A

outcome critically dependent on lifestyle factors - exposome

65
Q

should there be a screening program for haemochromatosis

A

a useful diagnostic test does NOT ⇒ a good population screening test

likelihood of discovering undiagnosed patient is <1 in 1000

no evidence of clinical benefit for treatment of asymptomatic carriers

66
Q

contraindications for screening

A

low positive predictive value e.g. haemochromatosis H63D

low population attributable risk (PAR) - proportion of total disease risk in the population attributable to the factor being screened for e.g. G6PDD mutations

low absolute risk e.g. FV Leiden thromboembolism relative risk for oral contraceptive users high, but absolute risk low as most are young people

no actionable knowledge - no way to improve prognosis

67
Q

principles of screening

A
68
Q

things to remember

A

GGE (33 decks)

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