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1 Genetics Flashcards

1
Q

definition of completely and incomplete penetrance

A
  • Complete - 100% chance of getting disease if have mutation

- Incomplete- won’t always get disease with mutation

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2
Q

Reasons for variable expression (2)

A
  • Modifier genes - affect how main gene affect individual

- Environmental factors - affect expression of gene, or affect other genes

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3
Q

Autosomal dominant examples (3)

A

APCKD - adult polycystic kidney disease
NF1 - neurofibromatosis 1
Inherited breast/ colon cancer

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4
Q

Autosomal recessive examples (5)

A 
CF - Cystic fibrosis
PKU - Phenylketonuria 
SMA - spinal muscular atrophy
Sickle cell anaemia
Congenital adrenal HYPERplasia
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5
Q

X recessive (2)

A

DMD

Congenital adrenal HYPOplasia

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6
Q

X dominant examples (3)

A

Vit D resistant rickets
Rett syndrome
Incontentia pigmenta

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7
Q 
Modes of inheritance patters:
AD
AR
XR
XD
A

AD - vertical
AR - horizontal
XR - knights move =affected male -> carrier female -> affected male
XD - vertical

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8
Q 
M:F ratio:
AD
AR
XR
XD
A

AD and AR = equal
XR = M»»>F
XR = 2:1 M:F

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9
Q

Definition and e.g. of genetic anticipation

A

Inc severity and dec. age onset in successive generations

Huntington's Disease (CAG)
Fragile X (CCG)
Myotonic dystrophy (CTG)
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10
Q

Genetic process of DMD

A

Excess CAG trinucleotide (codes for glutamine) repeats

  • > excess glutamine in hinting tin protein
  • > misfoldng for protein -> aggregates
  • > aggregates are neurotoxic so neutrons die
  • > affects nerve conduction
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11
Q

Definition and e.g. of pseudodominance

A

AR looks like AD if very high carrier freq. or consanguinity

Gilbert’s syndrome

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12
Q

Systems affected by mitochondrial inheritance and e.g.

A

High energy use - muscle, eyes, brain etc

Leigh’s disease

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13
Q

Definition of heteroplasmy (mitochondrial inheritance)

and threshold effect

A

Heteroplasmy = some mitochondrial DNA mutated, and some isn’t
Threshold effect = need to inherit enough mutated copies of mitochondrial DNA to have the phenotype

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14
Q

Genes in breast cancer

A

BRCA1/2 - chromosome 17/13
TP53

PALB and PTEN

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15
Q

Genes in ovarian cancer

A

BRCA1/2 - chromosome 17/13
MLH1
MSH 2

RAD51, PTEN, STK11, PTCH

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16
Q

Genes in HNPCC

A

MLH1
MSH 2/6
PMS2

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17
Q

Genes in FAP

A

APC gene - chromosome 5

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18
Q

Genes in MYH polyposis

A

Base excision repair gene affecting DNA glycosylase

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19
Q

No. polyps in HNPCC/ FAP/ MYH polyposis

A

HNPCC = <10
FAP = lots
MYH polyposis = 15-200

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20
Q

what colorectal cancer has a different inheritance pattern to the rest

A

MYH polyposis is autosomal recessive instead of dominant

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21
Q

What other cancers can be caused in HNPCC

A

endometrial (50%), ovarian (4%), gastric (5%)

Glial and urothelial

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22
Q

Prevention of breast cancer

A

Screening - exam and imaging

Prophylactic bilateral mastectomy (not 100% effective)/ (saplingo)oophorectomy

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23
Q

Prevention of ovarian cancer

A

Screening difficult

Prophylactic surgery

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24
Q

Prevention of HNPCC

A

2x year colonoscopy - age 25
2x year endoscopy - age 50
Aspirin reduces risk

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25
Q

Prevention of FAP

A

Bowel screening from age 11

If over 100 polyps - recommended bowel removal

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26
Q

Prevention of MYH polyposis

A

Colonoscopy every 2 years

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27
Q

Possible treatment of ovarian cancer and MOA

A

Olaparib (PARP inhibitor) - blocks 1 of 2 DNA repair pathways as mutation already blocks other –> cell death

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28
Q

What cancerous mutation is CHRPE common in (80%) and what is it

A

Congenital hypertrophy of retinal pigment epithelium - black spots in retina due to increased cell proliferation

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29
Q

Difference between tumour suppressor and protoonco genes

A

TSG:
>less of them but most likely in inherited cancers
>need 2 mutated copies
>normally inhibit cell cycle/ promote apoptosis/ caretake stability genes
>mutation decreases activity

POG:
>more of them but less likely to inherit 
>only need 1 mutated copy
>normally stimulate division/ growth
>mutation increases activity
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30
Q

what BRCA gene most likely causes:
Ovarian Ca
Male Br Ca

A 
Ovarian = 1
Male = 2
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31
Q 
Inheritance pattern of:
Huntingtons
Myotonic Dystrophy
Fragile X
Cystic fibrosis
NF1
DMD/BMD
A 
Huntingtons = AD + ga
Myotonic Dystrophy = AD + ga
Fragile X = AD + ga
Cystic fibrosis = AR
NF1 = AD
DMD/BMD = Xl- R
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32
Q

Gene mutations in:
Cystic fibrosis
NF1
DMD/BMD

A

Cystic fibrosis - phenylalanine (F508del) deletion on CFTR
NF1 - NF1 TSG gene
DMD/BMD - out/ in frame deletions of dystrophin gene

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33
Q

Gene mutations in:
Huntingtons
Myotonic Dystrophy
Fragile X

A

Huntingtons - CAG repeat = glutamine
Myotonic Dystrophy - CTG at 3’ UTR of DMPK
Fragile X - CCG at 5’ UTR of FMR1

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34
Q

Mechanism of disease in Myotonic Dystrophy

A

Abnormally long 3’ end of DMPK mRNA binds to other genes involved in gene splicing -> abnormal splicing of other genes (indirect effect)

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35
Q

Mechanism of disease in cystic fibrosis

A

F deletion in CFTR = abnormal protein for chloride ion channel, so it cant fold properly/ insert into cell membrane
Channel dysfunction -> lack of chloride ion transport -> thick secretions (pancreas and lung)

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36
Q

Mechanism of disease in DMD/BMD

A

Dystrophin normally binds F-actin and dystroglycan to strengthen muscle fibres. Abnormal dystrophin -> weak muscle fibres

37
Q

Symptoms/features of:
Trisomy 21 Down
Trisomy 18 Edward’s
Trisomy 13 Pateu

A

21 - learning difficulty, heart malformation, single palmar crease, hypothyroid

18 - small chin, clenched fist with overlapping fingers, heart/kidney/other organ malformation, learning difficulties

13- clenched fists, pst axial polydactyly, small eyes (micropthalia), learning difficulties, congenital heard disease, cleft palate/lip

38
Q

Symptoms/features of:

Huntingtons

A

Chorea
Psych problems
Dementia

39
Q

Symptoms/features of:

Myotonic Dystrophy

A

Myotonia
Muscle weakness
Cataracts

40
Q

Symptoms/features of:

Fragile X

A

Learning/ mental difficulties
ADHD/ autistic like behaviour
Long face - protruding jaw and forehead

41
Q

Symptoms/features of:

NF1

A

Cafe au lait macules (neurofibromas)
Lisch nodules on iris(>2)
Short stature and macrocephaly
Learning difficulties

42
Q

How to test for
cystic fibrosis
DMD/BMD

A

CF - neonatal DNA/ sweat test (Cl-)

DMD/BMD - serum creatine kinase (inc)

43
Q

Is genetic anticipation worse from mother/father in :
Huntingtons
Myotonic dystrophy

A 
HD = father
MD = mother
44
Q 
Type of DNA sequencing by:
aCGH
MLPA
Sanger
Allele specific (ARMS) PCR 
(Quantitive fluorescent) QF-PCR
Next generation
A 
aCGH = submicroscopic all chromosomes at once
MLPA = submicroscopic (known position)
Sanger = unknown point mutations, one gene at a time
Allele specific (ARMS) PCR = specific known point mutations
(Quantitive fluorescent) QF-PCR = aneuploidy/ polyploidy
Next generation = looks at whole genome
45
Q 
Describe:
Sanger sequencing
Allele specific PCR
array CGH
Quantitive fluorescent PCR
A

Sanger = comparing pt gene with reference gene (single gene) to find discrepancies

Allele specific PCR = creating primer to bind specifically to certain mutation being looked for (single gene)

Array CGH = comparing pt genome to reference and using colour coding (yellowfins same, red deletion, green addition)

QFPCR = DNA markers create peaks for each chromosome, to show how many of each chromosome are present

46
Q

Describe the Illumina method of Next gen sequencing

A

One coloured nucleotide is added and machine takes high resolution image.
Next nucleotide of a different colour is taken and machine takes another image.
This is repeated with the last 2 nucleotides to obtain the DNA sequence

47
Q

Describe the steps of data analysis (4)

A

> Raw data stored - FASTQ file
Compared with ref. genome and lined up/organised - BAM file
Variants identified when comparing BAM and ref - stored as VCF (variant call format)
SNPs (single nucleotide polymorphisms-harmless variants) removed to leave harmful variants

48
Q

Signs of DiGeorge/ Velocardial Facial/ 22q11.2del Syndrome

A 
CATCH22:
Cardiac abnormalities
Abnormal facial features - upsetting p. fissures/ prominent nose
Thymus hypoplasia
Cleft palate
Hypocalcemia
49
Q

Signs of Rubinstein Taybi/ 16p (part of) deletion syndrome

A

Microcephaly
Downslanting p. fissures
Broad thumbs
Large toes

50
Q

Method of preimplantation genetic diagnosis

And 2 ways of doing it

A

FISH - fluorescent probe
PCR - DNA probe

Take 1/2 cells out at very early stage, when still undifferentiated to check genetics

51
Q

Pros and cons of preimplantation genetic diagnosis

A

Pros:
Only implant unaffected embryos (IVF)
No need for TOM

Cons:
Multiple procedures/ hosp visits
Not available to all women
Miscarriage risk - <50% take home babies
May have a long wait
52
Q

What genetic testing can be used to test for XL Rec disorders and how

A

FISH
Red probe for Y ch
Green probe for X ch

53
Q

Criteria/ principles for screening programme (6)

A 
1- Clearly defined genetic disease
2- With appreciable frequency
3- advantage to early diagnosis
4- specific - few false positives
5- sensitive - few false negatives
6- benefits > costs
54
Q

Principles of genetic counselling (4)

A

1- Give advice and information
2- about investigation and interpreation
3- non directive advice
4- thinking about implications for relatives

55
Q

Prenatal genetic screening method and disease (1)

A

Down syndrome - by CUBS (combined US and biochemical screening)

  • US - nuchal translucency
  • maternal blood markers (excess cr 21?)
56
Q

Neonatal genetic screening method and diseases (3/5)

A

Mass spectrometry: PKU, MCADD

Immuno assay: CF, congenital hypothyroidism

HPLC: sickle cell

57
Q

Postnatal genetic screening diseases (2)

A

Population - thalassemia

Jewish - Tay Sachs

58
Q

Methods of diagnostic genetic tests (2)

A

CVS (chorionic villous sampling) - sample from placenta at 10-12 weeks, 1/50 miscarriage, result <1wk

Amniocentesis - sample from placenta at 16-18 weeks, 1/100 miscarriage, result 1-2wk

59
Q

Future prenatal genetic tests (2)

A

aCGH - compare all fetal DNA with normal reference DNA for submicroscopic insertion/deletion

NIPD/T - blood from mother, to test for free feral DNA
(trisomy 21, achondroplasia, Xl rec, sex determination)

60
Q

Situations where personalised medicine can be tailored using genetics (2)

A

1- treat after identifying SNPs to increase efficacy and decrease side effects
2- identify specific disease causing mutation to target e.g. CF (inherited)/ tumours (somatic)

61
Q

Treatments and targets for (personalised medicine):
CF
NSCLC
BrCa

A

CF - IVACAFTOR/ Kalydeco (reopens CFTR channel) - G551D gene
NSCLC - GETFITINIB/Iressa (targets EFGR)
BrCa - TRASTUZUMAB/Herceptin (targets HER2)

62
Q

Examples (and method) of diseases potentially treated by:
AON therapy
Gene editing (method only)
Base editing

A

AON therapy - DMD->BMD phenotype, by skipping axons 45&53 and altering gene splicing

Gene editing - using CRSPR-CAS9 guide RNA to find target sequence

Base editing - Marfan’s/ Beta-thalassemia, by swapping bases

63
Q

3 main factors in innate immunity

A

Soluble factors:
Antibacterial factors (lactoferrin and lysozyme)
Complement system

Cellular factors: scavenger macrophages (and other WBCs)

64
Q

Descrive antibacterial factors in innate immunity

A

Lysozyme = enzyme in mucosal surfaces which breaks down gram positive cell wall

Lactoferrin = protein in mucosal surfaces which collates iron (required by bacteria) so there is less free iron and bacteria cannot survive

65
Q

Describe complement in innate immunity

A

3 pathways:
1- classical: antibody:antigen complexes
2- lectin binding: to carbohydrates on pathogen cell surface
3- alternative: complement-causing molecule on pathogen surface

->complement activation ->

3: outcomes
1- attract inflammatory cells
2- opsonisation of pathogen
3- killing of pathogen

66
Q

Describe function of macrophages in innate immunity (3)

A

1) Phagocytosis
2) Antigen presentation - on MHC2 to CD4 in lymph node
3) Cytokine production -1=inflammatory (TNFa), 2=regulatory (IL10)

67
Q

What are pattern recognition receptors

A

Present on macrophage surface to identify common molecules found on pathogens, both intra/extracellularly

68
Q

Describe function of neutrophils in innate immunity(4)

A

1) Chemotaxis - migrate towards danger signals (complement/ chemokine etc)
2) Phagocytosis - digest and kill using proteases/lysozyme, reactive o2 species
3) Degranulation - kills pathogen and local cells
4) Die locally - produce pus

69
Q

Describe function of eosinophils in innate immunity(3)

A

1) Chemotaxis (chemokines=eotaxin)
2) Degranulation
3) Cytokine production (IL1/2/4/8, TNFa)

70
Q

Describe function of mast cells/ basophils in innate immunity(2)

A

1) Degranulation - preformed, containing histamine/cytokines

2) Cytokine release - preformed

71
Q

Describe function of dendritic cell in immunity(3)

A

1) Phagocytosis
2) Migration - to local lymph node
3) Antigen presentation - via MHC2

72
Q 
Describe functions of antibodies:
IgM
IgG
IgA
IgE
A

IgM - acute, low affinity, makes complement

IgG - chronic, high affinity, Fc binds to FcgR on phagocytes = opsonisation, can cross placenta

IgA - “antiseptic paint”, coats mucosal/ epithelial surfaces to block pathogen binging

IgE = Fc binds to FceR on mast cells, role in allergy/parasites

73
Q

Function of:
B cells
CD4 T cells
CD8 T cells

A

B cells: antibody production
CD4 T cells = helper cells, recruit other inflammatory cells
CD8 T cells = killer/ cytotoxic

74
Q

How do antibodies cause response

A

Fab region (light and heavy chain) binds to specific antigens
> Causes conformational change in Fc region
> Fc region (heavy chains) binds to respective receptor on phagocyte/immune cell
> Cell causes reaction e.g. degranulation (mast cells), phagocytosis (macrophages) etc.

75
Q

What happens to B cells after activation and clonal expansion (4 outcomes)

A

1- become plasma cells = antibody producing
2- isotope switching = make IgG/A/E (instead of IgM)
3- become memory B cells (high affinity)
4- affinity maturation = secrete high affinity antibodies

76
Q 
Cytokines produced and main functions of:
Th1
Th2
Th17
T-regulatory cells
A

> Th1 = IFNgamma (intracellular microbes)
Th2 = IL4,5,13 (Ab mediated response, helminths, allergy)
Th17 = IL17 (mucosal surfaces, bacteria)
T-regulatory cells = regulate other immune cells, including T cells and B cells

77
Q 
Where in the lymph node are:
B cell replication
B cell sampling 
T cell sampling 
Macrophages/ plasma cells
A

B cell replication - germinal centres
B cell sampling - primary lymphoid follicle
T cell sampling - paracortical area
Macrophages/ plasma cells - medullary cords

78
Q

Function of the spleen and lymph nodes

A

Lymph nodes - constant sampling of lymph by T and B cells

Spleen - similar to lymph nodes, and filtering products out of blood

79
Q

How is autoimmunity prevented

A

B cells and T cells are exposed to self-antigens in bone marrow/ thymus respectively, and if they have a high affinity/ response they die by apoptosis

80
Q

When activated by IgE, what is released by mast cells (6)?

A 
Tryptase
Toxins (e.g. histamine)
Cytokines
Chemokines
Leukotrines
Prostaglandins
81
Q

Early and late phases of type 1 hypersensitivity

A

Early - immediate:
Prostaglandins - vasodialtion/inc permeability (fluid in alveoli)
Histamine - smooth muscle swelling (airway constriction)

Late - hours/days:
T-cell/ immune cells - sustain smooth muscle contraction and tissue remodelling

82
Q

Mechanism of anaphylaxis

A

Systemic type 1 hypersensitivity
Massive vasodilation > hypotension > shock
Soft tissue swelling - airway

83
Q

Method of type 2/5 hypersensitivity

A

Antibodies attack self antigens

E.g. autoimmune/ drug induced haemolysis

Type 5 = same but against receptors, not antigens

84
Q

Method of type 3 hypersensitivity

A

Ag:Ab complexes form and deposit places causing inflammation against normal own cells, causing response

E.g. autoimmune/ drug allergy

85
Q

Method of type 4 hypersensitivity

A

Dendritic cells present self protein to Th1 cells, causing release of cytokines

E.g. contact dermatitis

86
Q

Hypersensitivity type and antibodies present in:
T1DM (type only)
Myasthenia graves

A

T1DM = type 2 and 4

Myasthenia gravis = type 2, IgG against AchR

87
Q

Antibodies and mechanism of rheumatoid arthritis

A

IgM and IgA = rheumatoid factor
Deposits, causes inflammation> release of PAD
>conversion of alanine to citrulline
Proteins attacked by anti-citrullinated Abs

88
Q

Environmental and genetic factors for autoimmune disease

A 
Environmental:
Geo - vit D (MS)
Mod - Smoking (RA)
Infection - molecular mimicry
Infection - exposure of Age due to tissue damage
Genetic:
MHC1 and 2 = HLA
Cytokines and their receptors
Transcription factors
Cell adhesion molecules
89
Q

Method of type 1 hypersensitivity

A

Mast cells with preformed IgE from previous exposure

Release granules on subsequent exposures (gets worse)

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