Scenario 33 Flashcards
What are mendelian disorders?
Caused by a single gene
What is compound heterozygosity?
Different mutations within the same gene (eg CF)
What are the key features of an autosomal dominant condition?
50% chance of passing on, affected individuals are heterozygous
KEY- MALE TO MALE TRANSMISSION
Variable penetrance, variable expression
Mutations can be Inherited from carriers or de novo
What are the key features of autosomal recessive conditions?
Both male and female affected
25% chance of passing on and 50% chance of carrier
25% unaffected
Common in consaginous relationships
What are the key features of X-linked recessive disorders
Only males related via the female line are usually affected
Women usually asymptomatic
1 in 2 chance that each son born to a carrier female is affected and 1 in 2 chance that each daughter will be a carrier
All daughters of an affected male are carriers
Sons of an affected male are not affected NO MALE TO MALE TRANSMISSION
Females can be affected- non random inactivation leading to a chance expression in certain tissues
What is X inactivation?
Only one X used per cell so one X is switched off before blastocyst implantation in female embryos
All of its daughter cells have the same X inactivated
What are the key features of X-linked dominant disorders
Males and females affected (more males)
Can be lethal in males
50% risk to offspring from affected mothers
All daughters of affected males inherit
No sons of affected males inherit (X comes from the mother) NO MALE TO MALE TRANSMISSION
What does a standard karyotype test show?
Changed chromosome number, structure, translocations
What is the limit of standard karyotype testing?
as small as 10Mb (chromosome is 100Mb)
How does aneuploidy arise?
When you get non dysjunction in a gamete (split unevenly) and that gamete fertilises
Such as Downs syndrome, patau syndrome (trisomy 13), edwards syndrome (trisomy 18) or sex chromosome eg Turners syndrome 45,X
What are the signs of Turners syndrome?
short stature, peripheral oedema, amenorrhoea, normal intelligence
Why does translocation not always have an effect?
It depends on which chromosomes are inherited can be unbalances with a partial monosomy or one chromosome and a trisomy of another
When is FISH used?
When you know specifically what you are looking for- fluorescent probe to highlight a particular abnormality
What conditions is FISH used to identify?
CATCH-22- conotruncal abnormality, cleft lip/palate, absent thymus and PT glands, learning difficulties
What are the advantages of comparative genomic hybridisation array?
Detailed karyotype to find small genomic inbalances in seemingly normal karyotypes e.g. Susceptibility Can see 100kb
When is single gene testing useful?
For diagnosis, management, recurrence risk and relative risk eg. Achondroplasia (FGFR mutation) or to distinguish between duchenne or becker muscular dystrophy
What is mocaicism
Later in development a cell acquires a mutation and all daughter cells from that one have the mutation but the others are normal- somatic can give mild features of a condition, germ line can give a future recurrence risk
What is NGS?
Test 95% of genome in one test- huge amount of data but ethical issues in finding out susceptibility information
What is incomplete penetrance?
The likleihood of the condition causing the phenotype so the risk of a child being affected is the probability of the mutant allele being inherited x penetrance
How do we calculate risk of autosomal recessive disorders in populations with no family history?
Hardy-Weinburg ratio
What are the key feature of the Hardy-Weinburg ration?
AA=pxp Aa=pq (twice) aa=qxq p+q=1 and p2+2pq+q2=1 disease incidence=qxq (square root to find q then work out p etc)
What are the key features of CVS?
taken in first trimester after 11 weeks, chromosome analysis after culture (2 weeks) 1-2% risk of miscarriage
What are the key features of amniocentesis?
10-20ml of amniotic fluid taken at 16 weeks cultured for 2 weeks 0.5-1% risk of miscarriage (would need a medical termination if decided)
What single base changes conserve the base chemistry?
C-T T-C G-A A-G
Why are there more transitions than transversions?
Because its easier to keep the base the same
What are common consequences of variants in splice recognition elements?
Depend on the relative strengths of the elements
Exon skipping, use of cryptic splice sites and intron retention
Where are some other sites of functional variation?
Promotors, untranslated regions or polyadenylation signals
What is an amorph?
Complete loss of gene function
What is a hypomorph?
Partial loss of gene function
Why do these loss of function variants arise?
Little or no protein produced, protein unstable or a residue/domain essential for function is missing or altered
What is haploinsufficiency?
Organism so sensitive to loss that 50% loss causes a phenotype
What is the dominant negative effect?
Not only does the protein lose its function but disrupts normal alleles function too
What is a somatic second hit?
Organism largely normal but somatic 2nd mutations give rare clones of null cells which are defective
What is an antimorph?
A variant where dominant alleles act in opposition to normal gene activity
What is a neomorphic gene?
Variants that cause a dominant gain of function different to normal function
What is genetic linkage?
That 2 DNA regions close together are more likely to be co-inherited in recombination
What is the LOD score?
Used to detect the presence of linkage =log10 L(linkage)/ L(no linkge)
>3 linkage
What do we do once we have worked out the 2 regions are linked?
Identify the genes located within and assess according to biological function, sequence them and find the causative mutation
What % of spontaneous abortions are aneuplodies?
50
What is the main cause of aneuploidy?
Meiotic non-dysjunction (mainly in females)
What are the main features of Downs syndrome?
mental disability, dysmorphic features, cardiac defects, 1 in 700 births, primary trisomy or translocation
What are Robertsonian Translocations?
Formed by the fusion of 2 acrocentic chromosomes (short p- 13,14,15,21 and 22) giving a chromosome number of 45 but a normal phenotype, happens in 2/1000 births and provides reproductive risks
2 long arms fuse and 2 short arms fuse- short one contains useless DNA and is lost leaving just the long- all the useful DNA present but may provide problems when being passed on
What are the main features of Edwards syndrome?
Severe mental disability, dysmorphic (micrognathia, prominent occiput), clenched overlapping fingers, rocker bottom heels and cardiac defects, 1 in 3000, 30% die in 1 month, 90% in 1 year, trisomy 18 and translocation
What are the main features of Patau syndrome?
severe mental disability, cleft lip and palate, holoprocencephaly, postaxial polydactyly, renal abnormalities, cardiac defects, 1 in 5000 45% die in 1 month, 95% in 1 year, trisomy 13 and translocation
What are the main features of Turner syndrome?
normal intelligence, webbed neck, broad chest, wide nipples, primary amenorrhoea, lack of secondary sexual characteristics, coarctation of the aorta, 1 in 5000, 45 X, 80% paternal orgin
What are the main features of Klinefelter syndrome?
taller than average, long limbs, 30-50% gynaecomastia, infertility, reduced IQ, 1 in 1000, 47XXY
What are reciprocal translocations?
Exchange of material between 2 non-homologous chromosomes (1 in 500) balanced carriers are generally phenotypically normal
What are the main features of Wolf-Hirschorn? (del 4p)
severe mental disability, frontal bossing, hypertelorism, carp shaped mouth, beaked nose
What are the main features of Cri du chat? (del 5p)
moderate to severe mental disability, cat like cry in infancy, slow growth
How do you detect sub microscopic deletions?
molecular cytogenic techniques, targeted testing based on clinical signs- FISH
What are the main features of Williams syndrome?
1 in 10000, elfin face, heart defects, hypercalcaemia, learning difficulties, 1.5Mb deletion of ELN and LIMK1 genes
What are the main features of Angelman syndrome?
severe mental disability, abnormal speech, movement or balance disorder, happy disposition, seizures, open mouth, protruding chin
Lack of maternally imprinted genes on chromosome 15
What are the main features of Prader-Willi syndrome?
Mild to moderate mental disability, hypotonia, failure to thrive, hypogonadism, obesity, growth retardation, small hands and feet, almond shaped eyes
Lack of paternally imprinted genes
What are cytogenetics?
The study of genetic constitution of cells through the visualisation and analysis of chromosomes- G banding, microarrays and other molecular techniques (FISH, MLPA) can be performed postnatally or prenatally
When would you use G banding?
When the signs are diagnostic of a balanced rearrangement (normal phenotype but infertile)
When would you use array CGH?
When a chromosome imbalance is suggested
What is in the human mitochondrial gene?
2 rRNA genes, 22 tRNA genes, 13 protein coding sequences, 1000-10000
How are mitochondria inherited?
Via the oocyte not the sperm
What is heteroplasmy?
The ratio of the no of mutant mitochondria: healthy mitochondria depends whether a phenotype will be seen
How can you predict the severity of a mitochondial disorder?
Roughly correlated with the mutant load in affected tissues
What is epigenetics?
The study of heritable changes that occur without a change in DNA sequence (bases stay the same), inherited faithfully through cell division
Are epigenetic changes reversible?
yes
How does differentiation by directing gene expression happen?
Epigenetics
What different mechanisms of epigenetic modifications are there?
DNA methylation, post-translational modifications to histone proteins and small/ non coding RNAs
How is the DNA methylated?
Methylation of one of the existing bases (cytosine) resulting in alterations in gene expression and phenotype- doesnt affect bonding with guanine
What diseases are linked to epigenetics?
Imprinting disorders, broad range of cancers and tumours, neurological disease (Rett, AD, PD, and HD), psychiatric disorders (autism, bipolar, schizophrenia), heart disease, AI disease
What are imprinted diseases?
Inherited form only one parent
150 known eg. PWS, AS, beck with-wiedemann syndrome, silver-russell syndrome, transient neonatal diabetes
Associated with imprinting- susceptibility to bipolar, mani depression, autism, schizophrenia
What happens if whole genome is from one parent not just a small part?
Parthenogenetic (2 maternal)- no placenta, hyperdifferentiation
Androgenetic (2 paternal)- placenta out of control
What are the main features of albrights hereditary osteodystrophy
associated with GNAS, problem with PTH, short metacarpals and metatarsals, phalanges and wide bones
What are the main features of Beckwith-Wiedemann Syndrome?
1 in 14,000 large tongues eyes, body size, hernia of the naval and small head
Cancer disposition
NLRP2
What are the main features of Silver-Russell syndrome?
Low birth weight, triangular face, poor appetite ICF2
What gene is involved in transient neonatal DM?
zfp57
