1 Genetics Flashcards
definition of completely and incomplete penetrance
- Complete - 100% chance of getting disease if have mutation
- Incomplete- won’t always get disease with mutation
Reasons for variable expression (2)
- Modifier genes - affect how main gene affect individual
- Environmental factors - affect expression of gene, or affect other genes
Autosomal dominant examples (3)
APCKD - adult polycystic kidney disease
NF1 - neurofibromatosis 1
Inherited breast/ colon cancer
Autosomal recessive examples (5)
CF - Cystic fibrosis PKU - Phenylketonuria SMA - spinal muscular atrophy Sickle cell anaemia Congenital adrenal HYPERplasia
X recessive (2)
DMD
Congenital adrenal HYPOplasia
X dominant examples (3)
Vit D resistant rickets
Rett syndrome
Incontentia pigmenta
Modes of inheritance patters: AD AR XR XD
AD - vertical
AR - horizontal
XR - knights move =affected male -> carrier female -> affected male
XD - vertical
M:F ratio: AD AR XR XD
AD and AR = equal
XR = M»»>F
XR = 2:1 M:F
Definition and e.g. of genetic anticipation
Inc severity and dec. age onset in successive generations
Huntington's Disease (CAG) Fragile X (CCG) Myotonic dystrophy (CTG)
Genetic process of DMD
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
Definition and e.g. of pseudodominance
AR looks like AD if very high carrier freq. or consanguinity
Gilbert’s syndrome
Systems affected by mitochondrial inheritance and e.g.
High energy use - muscle, eyes, brain etc
Leigh’s disease
Definition of heteroplasmy (mitochondrial inheritance)
and threshold effect
Heteroplasmy = some mitochondrial DNA mutated, and some isn’t
Threshold effect = need to inherit enough mutated copies of mitochondrial DNA to have the phenotype
Genes in breast cancer
BRCA1/2 - chromosome 17/13
TP53
PALB and PTEN
Genes in ovarian cancer
BRCA1/2 - chromosome 17/13
MLH1
MSH 2
RAD51, PTEN, STK11, PTCH
Genes in HNPCC
MLH1
MSH 2/6
PMS2
Genes in FAP
APC gene - chromosome 5
Genes in MYH polyposis
Base excision repair gene affecting DNA glycosylase
No. polyps in HNPCC/ FAP/ MYH polyposis
HNPCC = <10
FAP = lots
MYH polyposis = 15-200
what colorectal cancer has a different inheritance pattern to the rest
MYH polyposis is autosomal recessive instead of dominant
What other cancers can be caused in HNPCC
endometrial (50%), ovarian (4%), gastric (5%)
Glial and urothelial
Prevention of breast cancer
Screening - exam and imaging
Prophylactic bilateral mastectomy (not 100% effective)/ (saplingo)oophorectomy
Prevention of ovarian cancer
Screening difficult
Prophylactic surgery
Prevention of HNPCC
2x year colonoscopy - age 25
2x year endoscopy - age 50
Aspirin reduces risk
Prevention of FAP
Bowel screening from age 11
If over 100 polyps - recommended bowel removal
Prevention of MYH polyposis
Colonoscopy every 2 years
Possible treatment of ovarian cancer and MOA
Olaparib (PARP inhibitor) - blocks 1 of 2 DNA repair pathways as mutation already blocks other –> cell death
What cancerous mutation is CHRPE common in (80%) and what is it
Congenital hypertrophy of retinal pigment epithelium - black spots in retina due to increased cell proliferation
Difference between tumour suppressor and protoonco genes
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
what BRCA gene most likely causes:
Ovarian Ca
Male Br Ca
Ovarian = 1 Male = 2
Inheritance pattern of: Huntingtons Myotonic Dystrophy Fragile X Cystic fibrosis NF1 DMD/BMD
Huntingtons = AD + ga Myotonic Dystrophy = AD + ga Fragile X = AD + ga Cystic fibrosis = AR NF1 = AD DMD/BMD = Xl- R
Gene mutations in:
Cystic fibrosis
NF1
DMD/BMD
Cystic fibrosis - phenylalanine (F508del) deletion on CFTR
NF1 - NF1 TSG gene
DMD/BMD - out/ in frame deletions of dystrophin gene
Gene mutations in:
Huntingtons
Myotonic Dystrophy
Fragile X
Huntingtons - CAG repeat = glutamine
Myotonic Dystrophy - CTG at 3’ UTR of DMPK
Fragile X - CCG at 5’ UTR of FMR1
Mechanism of disease in Myotonic Dystrophy
Abnormally long 3’ end of DMPK mRNA binds to other genes involved in gene splicing -> abnormal splicing of other genes (indirect effect)
Mechanism of disease in cystic fibrosis
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)