Genetics Flashcards
What is the usual distribution pattern of an autosomal dominant condition
- one copy is enough to cause the disease
- is often present in every generation and shows a vertical pattern
- you can check there is male to male transmission as this rules out the possibility of it being x-linked
example of autosomal dominant inheritance
achondraplaisa
- inherited breast or colon cancer
- APKD
- NF1
- HD
variable expressivity and complete and incomplete penetrance in autosomal dominant conditions
variable expressivity = effects people to different extents even with the same genotype
complete penetrance = they always get the disorder if they have the faulty gene
incomplete penetrance = sometimes dont get the disorder despite having the faulty gene
gonadal mosaicism
gonads can often carry more than one copy of the mutated gene on sperm/eggs
Autosomal recessive
requires two faulty copies of the gene to cause disease, if one copy the individual becomes a carrier
- often shows a horizontal pattern -a prime examples of this is sickle cell disease
- both males and females effected
examples of AR conditions
- cystic fibrosis
- PKU
- spinal muscular atrophy
- congenital adrenal hyperplasia but NOT HYPO
- Wilsons disease
- tay-sacks disease
X-linked recessive inheritance
effects boys more than girls as they can compensate with their other x-chromosome
- knights move pattern NO MALE TO MALE
- occasional manifesting female carriers due to skewed x-inactivation
compound heterozygosity
the presence of two different mutated alleles at a particular gene locus
example of x-linked recessive
duchess muscular dystrophy
expected proportions of offspring of a female heterozygote for an x-linked recessive condition
50% of sons effected
50% daughters are carriers
expected proportions of offspring of a male heterozygote for an x-linked recessive condition
none of his sons effected as boys get their X chromosome from their mother but all his daughters are carriers
X-linked dominant inheritance
vitamin D resistant rickets
looks like AD but no male to male transmission
other examples:
- incontinentia rickets
- rett syndrome
genetic anticipation
- increasing severity and earlier age on onset in successive generations
in:
- HD
- Fragile x syndrome
- myotonic dystrophy
mitochondrial inheritance
- smaller genome
- circular
- 37 genes with no introns
inherited inly from the mother but can be to variable extents
syndromes often affect muscle, brain and eyes
LEIGHS DISEASE
how do you detect point mutations
DNA sequencing
- Sanger sequencing which analyses one gene at a time
- Next generation sequencing which can do all or many genes at once
Allele-specific (ARMS) PCR
- special PCR that analyses only specific known point mutations
how do you test for the detection of sub-microscopic duplications and deletions
MLPA = PCR method which targets a small group of specific known positions - chromosomal loci where there might be a deletion
Chromosomal microarray (CMA) = this is genome wide.
How do you rapidly detect aneuploidies
this is searching for an abnormal number of chromosomes that is not a multiple of 23 such as trisomy 18
done by quantitative fluorescent PCR (QF-PCR)
old chromosome-based analysis methods
karyotyping which uses a microscope at 4 million base pairs
FISH uses a specific DNA probe that binds to one specific location on a chromosome, so you need to know what location you want to look at
whole chromosome analysis
Karyotyping
QF-PCR
Sub-microscopic deletions and duplications
FISH
MLPA - if you know the position
Chromosomal micro-array if you dont
point mutations
DNA sequencing or ARMS
NGS method
illumina method
- hundreds of millions of DNA fragments sequenced at once
- on a “flow cell”
huntingtons disease
onset between 30 and 50
progressive chorea, dementia and psychiatric symptoms
AD with genetic anticipation
caused by a CAG repeat unit within the coding sequence which encodes a polyglutamine tract and this expansion causes insoluble protein aggregates and neurotoxicity
myotonic dystrophy
AD also with genetic anticipation
- progressive muscle weakness in early adulthood
- can also result in myotonia and cataracts
unstable mutation of a CTG repeat
- abnormal DMPK mRNA which has an indirect toxic effect upon splicing of other genes e.g. the chloride ion channel CLCN1 gene which causes myotonia
cystic fibrosis
AR
Recurrent lung infections
exocrine pancreatic insufficiency
screening in newborns by immunoreactive trypsin IRT) level
This can be confirmed by DNA testing for CF mutations and/or sweat testing for increased chloride conc
CFTR mutations which result in defective chloride ion channels and therefore an increased thickness of secretions
most common is F508del
NF1 common presentations
cafe au lait macules and neurofibromas, short stature and macrocephaly
learning difficulty in 30%
Lisch nodules (2 or more) that can be seen on a slit-lamp
what is the pathology of duchess muscular dystrophy
creatine kinase leaks out of damaged muscle fibres into serum (into blood)
boys with DMD will have massively increased levels of creatine kinase in serum from birth before any symptoms become noticeable
Duchene muscular dystrophy vs Becker muscular dystrophy
DMD:
- onset at roughly 3
- wheelchair by 12
BMD:
- onset at roughly 11
- Wheelchair much later or not at all
Fragile X syndrome
X-linked recessive most common cause of inherited learning disability
what is a full mutation in fragile x syndrome
> 200
Edwards syndrome
- trisomy 18
- small chin
- clenched hands with overlapping fingers
- malformations of heart, kidney and other organs
patau syndrome
- trisomy 13
- congee heart disease is usual
- many die within a month
- cleft lip & palate
micropthalmia
abnormal ears
clenched fists
what is the role of tumour suppressor genes
inhibit progression through the cell cycle
some promote apoptosis
some act as DNA repair genes
porto-oncogenes role
normally stimulate the cell cycle, these when effected by a gain of function mutation can lead to tumour formation
what happens when a mutation occurs in the tumour suppressor genes
these mutations result in a loss of function and usually requires loss of a normal allele (gene copy) (REFER TO TWO HIT THEORY)
what are DNA repair genes
these are a sub-type of TSG which act to minimise genetic alterations
important in breast/ovarian and colorectal hereditary cancer predisposition syndromes
what is the cause of most inherited cancer predispositions
due to the inheritance of an altered TSG which then involves the subsequent activation of the wild-type (normal) allele, THIS IS THE TWO HIT HYPOTHESIS
If a patient has breast and ovarian cancer history what is the likely mutation
BRCA1
If there is male breast cancer present in the family what is the likely mutation
BRCA2
If you have a BRCA1 mutation what is the likelihood of developing breast cancer by the age of 70
50-80% this is an example of incomplete penetrance
and 20-50% for ovarian cancer
If you have a BRCA2 mutation what is the likelihood of developing breast cancer by the age of 70
50-80% breast cancer
10-20% ovarian
5-6% breast cancer in men
preventative measures for breast cancer
examinations
screening such as mammography or MRI
if you have BRCA1 OR BRCA2 mutations then you may be offered
- prophylactic bilateral mastectomies
- prophylactic oophorectomies (removal of the ovaries)
treatment for ovarian cancer
PARP
common colon cancer mutation
hereditary non-polyposis colon cancer also known as Lynch syndrome
Some FAP = familial adenomatous polyposis
hereditary non-polyposis colon cancer also known as Lynch syndrome
- usually only a few polyps, has to be less than 10, in the ovary stomach or uterus
this is due to inheritance mutation in MMR system genes
what genes cause HNPCC
MLH1
MSH2
MSH6
PMS2
FAP
congenital hypertrophy of the retinal pigment epithelium
from APC gene on chromosome 5
patients get annual bowl screening from age 11
MYH/MUTYH polyposis
AR
2 yearly colonoscopy
like a mild form of FAP
Li Fraumeni syndrome
rare AD cancer predisposition syndrome
- great cancer
- brain tumours
- sarcoma
- leukaemia
- adrenocortical carcinoma
mutations in TP53 gene
what would you want to know from a patients clinical history
what were the age of onset of symptoms and how is the progression
what would you want to know from a patients family history
consanguinity ? miscarriages? still births?
what would you want to note from a patients examination
- any dysmorphic features
- normal growth (height, occipital-frontal circumference - OFC)
examples of dysmorphic features
smooth philtrum
correct number of fingers and toes
are they joined (syndactyly)
polydactyly (too many?
eyes:
slant of palpebral fissures
spacing
ears:
- size, shape, position (are they low set)
- rotated anteriorly or posteriorly
hands
- palmar creases
Rubinstein Taybi syndrome
down slanting palpebral fissures
microcephaly
broad thumbs and big toes
intellectual disability
What are some new/future developments for treatment and testing in genetics
more use of non-invasive and prenatal diagnosis NIPD (on maternal plasma and free fetal DNA)
this could aid with
- testing for metal sex determination for X linked conditions as you would test for Y chromosome DNA
- for paternal mutations could search for FGFR3
Can also test for anaeploidy which can be confirmed by CVS or amnio
Increase use of next gen sequencing of gene panels which tests whole exomes and while genomes
more gene therapy
more precision medicine
what is precision medicine
this would be the selection of medication after analysing DNA to increase the efficacy and reduce the side effects
examples of this include treatment for CF
if you undergo gene testing for the G551D mutation which blocks the opening of the CFTR chloride ion channel the ivacaftor (kalydeco) can reopen the channel so this would be prescribed and you would know it would work
use of precision medicine in cancer
the use of one or more clinical biomarkers to identify therapies more suited for specific patients such as in NSCLC (the presence of particular EGFR gene mutations indicate that tumour may respond to tyrosine kinase inhibitors
what are the current gene therapy strategies
treating the gene or its expression (transcription, splicing and translation
OR
replacing the gene
what are some future therapies for DMD
the use of a drug to permit read-through of premature stop codons such as Ataluren (this is a small molecule that may cause read through of premature stop codons in 10-15% of cases of DMD allowing the ribosome to finish synthesising the protein (dystrophin)) or PTC124
genetic heterogeneity
one disorder having several genetic causes
Pleiotropy
one gene causes more than one condition or train such as RET gene causes MEN2 (AD) and also Hirschprungs Disease (AR)
