Genetics Flashcards
What is nonsense mediated decay?
Getting rid of proteins produced that don’t conform to normal standards (either stop being too early or too late)
What is polygenic risk?
Multiple genes contributing towards familiar risk
What is leucocornea?
White eye in retinoblastoma
What happens in hereditary non-polyposis colon cancer? (HNPCC/lynch syndrome)
Mutation in mistmatch repair genes
Excess of cancers in adenoma carincoma sequence
Early CRC
Effects proximal colon
What is a germline mutation?
Where mutation is present in egg/sperm and are henceforth heredtary
Cause cancer family syndromes
What is an oncogne?
A gene that controls cell processes that, if it mutates, will be enough to start the cancer process
What are the lifetime cancer risks of the BRCA genes?
Breast - 60-80% (early onset)
Secondary primary breast cancer - 40-60%
Ovarian 20-50%
Increased risk of prostate + breast cancer in men
When do you suspect hereditary cancer syndrome?
Cancer in 2+ relatives Early age of diagnosis Multiple primary tumours Bilateral or multiple rare cancers Charactersitc pattern of tumours Evidence of autosomal dominant transmission
What are the options for breast cancer surveillance?
Early clinical surveillance 5yrs before 1st cancer in family
Annual clinical breast exams
Mammography Every 2 yrs from 35-40, yearly from 40-50
Every 18 months if high risk from 50
What is the benefit of a prophylatic oophrectomy?
Eliminates risk of primary ovarian cancer (peritoneal cancers can still occur)
Risk of subsequent BRCA halved
How is colorectal cancer surveyed in lynch syndrmoe?
Colonoscopy every 2 years from 25 if high risk
If moderate risk once at 35 and once at 55
How is endometrial cancer screened for in lynch syndrome?
Transvaginal ultrasound
No recommendations
What are the limitations of genetic testing?
doesn’t detect all mutations
Continued risk of sporadic cancer
Efficacy of interventions variable
May result in psychosocial/economic harm
What cancers are associated with Li-Fraumeni syndrome?
Soft-tissue sarcoma Osteosarcoma Breast cancer Brain/CNS tumours Adrencortical carcinoma Acute luekemia
What are the modes of inheritance for multi-system disorders?
Any possible eg - Chromosomal Single gene Poly gene
What are some important multi-system disorders?
NF1 Myotonic dystrophy Tuberous clerosis CF Downs
How do disorders cause mlti-system involvement?
As several (or just one) gene with diverse functions are involved This can be widely expressed in different tissues >However expression in tissues can be different
What are the mechanisms of adult onset genetic disease?
Single gene
Chromosomal
Mitochondrial
Multifactorial
What are some common problems in multi-system disease?
Variable expression within + between families
Present to a large number of specialists
FH easily missed
What gene pattern is neurofibromatosis type 1 (NF1)?
Autosomal dominant
17q tumour supressor gene affected
What is the diagnostic criteria for NF1 (neurofibromatosis type 1)?
2+ of: café au lait spots - 6 or more neurofibromas - 2 or more axillary freckling Lisch nodules (specks in iris) optic glioma thinning of long bone cortex family history
What other features can accompany NF1?
Macrocephaly Short sature Dysmorphic features Learning difficulties Epilepsy Scoliosis Raised BP Neoplasia
How do you manage NF1?
Annual review of affected individuals + at risk children until diagnosis excluded Check for: BP Spine for scoliosis Tibia for unusua angulation Visual acuity/fields Educational assesment
What are the main features of NF2?
Acoustic neuromas (often bilateral)
CNS + spinal tumours
A few CAL spots
WHat chromosome is NF2 found on?
Chromosome 22
What is tuberous sclerosis?
An autosomal dominant disease with a triad of:
Epilepsy
Learning difficulty
Skin lesions
What is the penetrance of tuberous sclerosis?
Almost full penetrance
What genes cause TS?
TSC1
TSC2
What are the clinical features of TS?
Has variable expression Learning difficulty common Seizures common - infantile spasms, myoclonic seizures Skin lesions Kidney cysts Phakomas in eyes Rhabdomyomas in heart
What are the skin lesions in TS?
depigmented macules angiofibromas fibrous plaque forehead shagreen patches ungual fibromas
How do you screen relatives for TS?
Cranial MR scan
Renal USS
Echocardiogram
Clinical examination
What is myotonic dystophy?
An autosomal dominant disease
Increases in severity with each generation
What are the main symptoms of myotonic dystrophy?
Bilateral late-onset cataract Muscles weakness, stiffness + myotonia Low motivation Heart block Congneitcal motonic dystrophy - can lead to death
Why is risk estimation more difficult in multifacotrial conditions?
Often polygenic component interacting with environmental factors
Penetrance may vary
>Even if risk allele determined may no have disease
What is penetrance?
The chance of having a genetic disease if you have the genes responsibile for it
What is the mean age of onset for amyotophic lateral sclerosis?
55years (can be younger in familial forms)
What are the clinical features of ALS?
Progressive muscle weakness, wasting + increasing reflexes >Upper + lower motor signs Limb + bulbar muscle involvements Pure motor signs with fasiculations Cognition spared Death eventually due to resp failure
What is the only identified gene that causes ALS (accounts for only 2% of cases)?
Copper/zinc superoxide dismutase (SOD) mutations
Where are SOD 1, 2 and 3 located?
SOD1 in cytoplasm
SOD2 in mitochondria (manganese)
SOD3 in extracellular
What chromosomes are SOD genes located?
21
6
4
What is the function of SOD?
Protects cells from free radical damage As well as protecting from DNA damage, Ionising radiation damage Protein denaturation Lipid peroxidation
What is the penetrance of ALS?
Incomplete
What is the prognosis of ALS?
As there is no cure or satisfactory treatment, pretty poor
What are the symptoms of Huntington’s?
Poor planning + memory Subcortical dementia Not classical dementia Personality changes Psychiatric disease - depression, paranoia, psychosis
When does huntingtons present?
Onset late 30s-40s but variable
What is the penetration of Huntingtons?
Fully penetrant
What are the disadvantages of predictive testing (positive outcome)?
Removes hope Continues uncertainty (when, not if) Known risk to offspring Impact on self/family/friends Potential problems with insurance/mortgage
What are the disadvantages of predictive testing if negative result?
Survivour guilt
Expectations of a “good” result
Do you test children for Huntingtons?
No.
As only 25% of people choose to be tested overall, testing a child would take away their right to not know if that was their wish
