Genetics Flashcards
(107 cards)
1
Q
Describe penetrance
A
Penetrant – show signs of disorder
Non-penetrant - don’t show signs of disorder – “skips” generation
2
Q
describe expressivity
A
variation in clinical presentation/phenotype between patients
3
Q
describe x-linked inheritance
A
• More than one generation affected • No male to male transmission • Usually only males affected • Types o Duchenne muscular dystrophy o Fragile x syndrome
• Carrier females can be affected due to x-inactivation which is a random process
4
Q
describe autosomal dominant
A
- Involvement of more than one generation
- Male to male transmission
- Males and females affected equally
5
Q
describe autosomal recessive
A
- One or more affected children with unaffected parents
- Usually only one generation affected
- Males and females affected with equal frequency and severity
- A higher incidence of consanguinity
6
Q
what is the hardy weinburg equation
A
p 2 +2pq + q 2 = 1
Where p = normal allele and q = disease allele
q2 is the disease incidence
7
Q
what is packing ratio
A
length of native DNA strand / length after condensation
8
Q
what packing ratio do nucleosomes have
A
around 6
9
Q
what is the 30nm fibre
A
coiling of beads in a helical structure
This structure increases the packing ratio to about 40.
10
Q
what is the packing ratio in interphase chromosomes
A
about 1000
11
Q
what is the most condensed state of human chromosomes
A
in the mitotic phase of cell division (after the chromosomes are replicated and the copies held together as sister chromatids) where they have a packing ratio of 7000-10,000 at which point – with the use of appropriate fluorescent or cytochemical stains - they can be observed by standard light microscopy.
12
Q
what is the role of condensin I
A
lateral compaction of chromosomes in metaphase
13
Q
what is the role of condensin II
A
axial shortening of chromosomes in prophase
14
Q
what is cohesin involved with
A
metaphase chromosomes separating
15
Q
what does the pulling of kinetochores cause
A
Kinetochore exerts a pulling force and when this reaches a certain force, a signal causes cohesin molecules to separate leading to neat pulling to the poles
16
Q
what is trisomy 21
A
down syndrome
17
Q
what is trisomy 18
A
edward syndrome
18
Q
what is trisomy 13
A
patau syndrome
19
Q
how do you name a karyotype
A
- Number of total chromosomes
- Then sex e.g. XX or XY
- And the a +21 for down syndrome for example
20
Q
what is Klinefelter syndrome
A
boys with an extra X chromosome – XXY
21
Q
what is turner syndrome
A
45 chromosomes – only 1 X in girls
22
Q
what can XYY cause
A
impulse control problems
23
Q
what can XXX cause
A
mild cognitive impairment
24
Q
what is the difference between male and female meiosis
A
Male meiosis creates 4 sperm but female only produces one egg
25
what happens in meiosis
Homologous chromosomes join together
Homologous recombination occurs to make double stranded breaks to swap material
First meiotic division is the separation into homologous chromosomes and second divides these
26
what is the difference between MI and MII non-disjunction
MI non-disjunction leads to no separation of the pairs of homologous chromosomes leading to cells with 48 chromosomes and then these split to make 2 gametes with 24 chromosomes and 2 with 22 which are incompatible with life
MII non-disjunction leads to two gametes with 23, one with 24 and one with 22
27
what is reciprocal translocation
Non-homologous end-joining between chromosomes – where two non-homologous chromosomes are close to each other in normal homologous repair and the ends of the chromosomes are swapped
This doesn’t cause health problems but affect reproductive health – reduced sperm count in males
Also cause major malformation in the children of parents with reciprocal translocations
Genes can be interrupted by reciprocal translocation which are usually de novo and leaves them with only one functioning copy of the gene
28
Non-allelic homologous recombination
* Most of the human genome is unique
* There are some unusual parts where there are two identical copies in a homologue
* If these line up wrong during homologous recombination it can lead to deletions and duplications
29
what are acrocentric chromosomes and which are they
where the centromere is very near to one end of the chromosome
13, 14, 15, 21, 22
Others are metacentric
30
what are the ends of acrocentric chromosomes useful for
important for making ribosomes
All these genes to make ribosome parts are somewhat redundant which can be shown naturally by Robertsonian translocations.
This is where the short arms of two acrocentric chromosomes fuse which means that the cell only has 45 chromosomes. Again these are balanced but can lead to some infertility
31
where does DNA methylation most often occur
at CpG dinucleotides
32
what does a gene commonly have
• A promotor region, this may contain a TATA box or
CpG island.
• Exons, which contain the sequence transcribed to
mRNA.
• Introns, which contain sequence that is removed
by splicing after transcription.
• 5’ and 3’ untranslated regions.
• Start and stop codons.
33
• Amount of protein product from a gene is controlled by:
* Rate of Transcription. Amount of mRNA produced.
* Splicing – controlled by splice consensus sequences at intron/exon boundaries.
* Stability of mRNA.
* Stability of protein product made.
* Correct localisation of protein product.
* Correct post-translational modification of protein product.
34
what is a polymorphism
a DNA variant present in the population at a significant frequency.
A polymorphism may be a single nucleotide polymorphism (SNP), insertion or deletion.
35
what is linkage
the tendency of two sequence variants to be inherited together
This is because of their physical proximity on the same chromosome
36
A Mutation in a gene can be:
* Complete deletion of a gene.
* A base change causing an amino acid change or a premature stop.
* A small insertion or deletion, this can be in frame or out of frame.
* A mutation that affects a splice site.
* A mutation in the promotor sequence or in other regulatory elements.
37
A mutation can affect a protein in different ways to cause disease:
* Abolish protein product.
* Abolish protein function. – this may lead to a dominant negative effect.
* Reduce protein function.
* Affect transport or post-translational modification of a protein.
* Activate a protein.
38
what is Allelic Heterogeneity
an example is that the same disease phenotype is often caused by different mutations in the same gene
39
what is locus heterogeneity
The same disease phenotype can be caused by mutations in different genes
40
what can mutations in the same gene occasionally cause
a different disease phenotype, depending on the effect the mutation has on the protein
41
A mutation is more likely to be causative of a genetic disease if:
* It can be demonstrated to have an effect on protein production or function.
* It is present in all the affected individuals in a family.
* It is in a conserved region of the protein.
* It does not occur as a population polymorphism.
42
types of mutations
* Deletions
* Ranges from 1bp to megabases
• Insertions
• Ranges vary can be as small as 1bp up to
megabases
• Duplication and inversions
• Single base pair substitutions (point mutations)
• Frameshifts
• Caused by deletions, insertions or splice site
errors
* Dynamic mutations
* Tandem repeats
43
describe synonymous mutations
– changes a codon into another that specifies the same amino acid as the original codon
– due to redundancies within genetic code
44
describe non-synonymous mutations
– changes a codon into another that specifies a
different amino acid to that of the original codon
– types
• Missense mutations
• replace one amino acid with another
• Nonsense mutations
• replace an amino acid codon with a stop
codon
* Splice site mutations
* create or destroy splicing signals
45
what do you have to think about with missense mutations
• Has it caused a conserved or non-conservative change in amino acid
– Change in polarity
– Change in hydrophobicity
46
what is the grantham matrix?
* Method in calculating the significance of the amino acid substitution
* The bigger the score the more likely that the missense mutation has caused a change in the resultant protein structure
47
what is co-segregation
if there are more than 5 affected members in the family with that gene change then you can say with 98% certainty that the gene change is pathogenic
48
describe splice site mutations
* The nucleotides at the start and end of an intron are highly conserved across species
* Mutations in splice donor site cause the post-transcriptional mechanism fails to recognize the start of an intron and will not splice it out – leads to a mRNA with an intron included – introns can be quite large which leads to protein abnormality
* Mutations in splice acceptor site can lead to exon skipping
49
a mutation can cause disease through:
• Loss of function (Abolition) of gene product
o Due to non-functioning or truncated protein
Usually due to intragenic mutations
• Marfan syndrome, Duchennes
muscular dystrophy
o Haploinsufficiency
Usually refer to submicroscopic
chromosomal deletions
• William syndrome
o Dominant negative
Deafness syndromes, Collagen disorders
• Modification of gene product
o Creating a poorly functioning protein
Beckers muscular dystrophy
o Abnormal activation of protein (overexpression)
Cancer genes
o Gain of function of protein (novel function)
Huntington disease, cancer genes
philadelphilia chromosome-fusion protein)
50
describe dominant negative
* Special class of loss of function
* The mutation produces a none functioning protein
* The none functioning protein interferes with the protein of the normal functioning homologous gene
* Resulting in no effective gene product
51
describe some types of DNA testing
• Direct testing:
o The DNA from a consultand is tested to see whether or not it contains a given pathogenic mutation.
• Indirect testing (gene tracking):
o Linked markers are used in family studies to discover if the consultand inherited the disease carrying chromosome/allele from a parent.
52
describe PCR
* Very efficient at amplification of template DNA to yield products for analysis.
* DNA can be extracted from various sources blood specimens, mouthwash or tissue specimens.
* Only requires small amounts of patient genomic DNA.
* Best at amplifying small specific segments of DNA
• Steps
o Heated to 95° to split strands
o Cooled to 60° to allow primers to anneal
o Then to 72° to allow taq polymerase to synthesise the complementary strands from free nucleotides
o This is repeated and the number of target sequences grows exponentially compared to the longer strands which after dozens of cycles is essentially pure target sequence
• Requires knowledge of targeted sequence
o To be able to design primers for amplification of target DNA
• Specificity is dictated by two short (~25 bases) synthetic single stranded DNA molecules or oligonucleotides (primers)
• Mis-priming
o Amplification of none target DNA
• Preferential amplification of normal allele (PCR drop out)
53
what comes after PCR
* Sanger Sequencing
* Next Generation Sequencing (massive parallel sequencing)
* Gel electrophoresis
54
describe Sanger Sequencing
o Gold standard
o Well established (>20years)
o Robust
o one reaction = 1 sequencing reaction
o optimal sequencing length (500bp-900bp)
o sequencing 1 gene will require multiple reactions
o labour intensive and time consuming
55
describe Next Generation Sequencing (massive parallel sequencing)
o Very expensive (getting cheaper)
o High volume of data
o High number of genetic variants of unknown significance
o Require sophisticated bio-informatics
o Good for multi-gene analysis (exome or whole genome)
56
describe Gel electrophoresis in huntingtons
PCR amplification of CAG repeat within the Huntington gene on chromosome 4
Amplification of variable repeat gives a range of sizes or alleles.
PCR products resolved on high resolution poly-acrylamide gel on automatic laser fluorescent sequencer for exact sizing.
Distinct size ranges are seen for affected HD population and normal population.
57
what is the first spike in huntingtons CAG repeat electropherogram
5 CAG repeats and each spike after is one repeat
58
what is the normal range for huntingtons for CAG repeats
* Normal individuals in our population have alleles in the 8 to 35 CAG repeat range.
* A repeat size of 36 repeats or greater is diagnostic of HD.
* Alleles between 36 and 39 repeats are frequently associated with later onset of symptoms.
* Alleles between 27 and 35 repeats are potentially unstable and rare expansions into the affected range have been seen.
59
what is exclusion testing
where the person getting the test does not want to know if they are at risk of developing the disease but want to have children that are free of it
if the parent with the condition is known you can tell which alleles would be passed onto the parents grandchildren which could be a high risk gene
this does not confirm whether the person getting the test has the condition
60
what type of testing should you do
• Direct DNA sequencing:
o PCR fragments of 150-850 bp for mutation scanning
o For confirmation of mutation
• Next Gen sequencing: Multi-gene analysis
• PCR then Gel electrophoresis
o fluorescent sizing of products:
o trinucleotide repeats
o microsatellite repeats (up to 400bp)
• Southern blotting of digested DNA: methylation sensitivity and larger size range. 500bp to 20kb.
61
what are the types of prenatal diagnosis
Chorionic Villus Sampling (CVS)
Amniocentesis
Foetal sexing on maternal blood.
Preimplantation Genetic Diagnosis (PGD)
62
what is chorionic Villus Sampling (CVS)
CVS will provide a piece of placenta, providing material for DNA extraction and chromosome analysis. It is generally performed from about 11 weeks gestation and carries a miscarriage risk of around 1.5 - 2% as a result of the test.
As DNA can be extracted directly without having to culture the villi a result is generally available within 3 days providing that the test is PCR based.
63
what is amniocentesis
Amniocentesis is a diagnostic test that involves the removal of 10-20mls of amniotic fluid under ultrasound control. The fluid contains cells from the baby and placental membranes which can be cultured for chromosome analysis or can provide a source of DNA for molecular analysis. Amniocentesis is generally performed from 15 weeks gestation onwards and carries a 0.5-1% miscarriage risk.
Amnio-PCR is a rapid, PCR based test involving amplification of polymorphic markers on chromosomes 21,18 and 13 directly from amniotic fluid. The test is based on a limited number of PCR cycles which allows quantification of results.
64
what is foetal sexing on maternal blood
Cell-free fetal DNA (cffDNA) originates from placental trophoblast and is shed into the maternal blood stream. cffDNA circulates freely in the maternal blood stream and can be used for non-invasive prenatal diagnosis. The amount of cffDNA increases as the pregnancy progresses, representing 3 – 6% of total DNA in maternal plasma and is cleared rapidly from the maternal circulation post delivery. From 8 weeks gestation a maternal blood sample can be analysed to detect a Y-specific sequence from a male foetus. This technique is currently used for the early non-invasive prenatal determination of sex for foetuses at risk of X-linked disorders with the aim to avoid invasive CVS for foetuses predicted to be female.
65
what is preimplantation genetic diagnosis (PGD)
PGD is a technique designed to help couples at risk of having a child with a single gene disorder or a chromosomal disorder . It involves using in vitro fertilisation (IVF) to create embyos from the eggs and sperm of that couple. Each embryo is then tested for the particular genetic disorder and one unaffected embryo is transferred into the womb, in the hope that a pregnancy will occur.
66
what is antenatal screening
Antenatal screening is concerned with the identification of pregnancies at increased risk of problems. Where appropriate it may lead to prenatal diagnosis being performed.
67
what does antenatal screening look for
Haemoglobinopathies
| Screening for Trisomy 21, Trisomy 18 and Neural tube defects
68
how are haemoglobinopathies screened
All pregnant women will be offered screening for thalassaemia based on a formal process of inspection of routine blood indices. Additionally, using a Family Origin (Ancestry) Questionnaire (FOQ) to assess risk status, women in high risk groups, or women whose partners are in high risk groups, will be offered screening for sickle cell disorders and other haemoglobin variants
69
how is screening for Trisomy 21, Trisomy 18 and Neural tube defects done
All women in SE Scotland are offered a dating ultrasound, first trimester screening for Down’s syndrome and also a detailed second trimester ultrasound examination. First trimester screening combines maternal age, nuchal translucency measurement (ultrasound measurement of the thickness of the fold at the back of the fetal neck) and maternal serum markers Free Human Chorionic Gonadotrophin (HCG) and Pregnancy-associated plasma protein A (PAPP-A). It is carried out between 11 weeks and 13+6 weeks gestation.
Women who missed first trimester screening can be offered second trimester screening. For this maternal blood is taken between 15 and 20+6 weeks gestation to measure Alpha-fetoprotein (AFP), HCG, unconjugated oestradiol and inhibin A.A high hCG:AFP ratio increases the chance that the fetus is affected by Down syndrome.
An AFP of more than 2 multiples of the median (MoM) corrected for maternal weight indicates an increased risk of neural tube defect. Detailed second trimester ultrasound scanning should identify over 90% neural tube defects.
Ultrasound examinations screening for fetal anomaly in low risk women are performed between 18 and 20+6 weeks gestation.
70
describe retinoblastoma inheritance
Retinoblastoma inheritance is autosomal dominant
Very high likelihood (90%) that if inherited will lead to tumours
10% of retinoblastoma is familial
71
what is Knudson’s Two-hit Hypothesis
Based on observation of retinoblastoma (a childhood eye tumour) but applicable to any cancer caused by mutations in a tumour suppressor gene.
In any one cell both copies of the tumour suppressor gene must be inactivated or lost before neoplastic transformation can take place. If an individual has a germline mutation (the first “hit”) then a second somatic mutation in the same cell (“second hit”) will lead to transformation. If an individual has 2 good copies of the tumour suppressor gene then two separate somatic “hits” will be required in the same cell before neoplastic transformation will occur.
An individual with a germline mutation in a tumour suppressor gene is therefore much more vulnerable to a second somatic mutation and tumour formation.
72
describe neurofibromatosis
* Multi system disorder
* Dominant
* Fully penetrant
* affects about 1 in 2,500 of the UK population
* Highly variable expression between affected individuals in the family
* 50% cases new mutation
• Neurofibromas
o Discrete cutaneous neurofibroma of dermis or epidermis
o Discrete subcutaneous neurofibromas that lie deeper in the skin
o Deep nodular neurofibromas
o Diffuse plexiform neurofibromas
The NF1 gene on chromosome 17 encodes the protein Neurofibromin
• Neurofibromin suppresses Ras, a potent activator of cell growth and proliferation
• Cancer predisposition
o Malignant tumor of the peripheral nerve sheath
Life time risk of 13%
Usually from pre-existing plexiform neurofibroma
o Astrocytoma 2%
o Phaeochromocytoma 0.7%
o Rhabdomyosarcoma 1.4%
73
what are the findings in neurofibromatosis
```
• Ophthalmological findings
o Lisch Nodules - 90%
o Optic Glioma - 15%
Usually asymptomatic
Can present with deteriorating vision
```
```
• Skeletal problems
o Scoliosis - 10%
Usually mild
Very small number with severe presentation
o Pseudarthrosis - 1%
Usually of long bones
Pathological fractures
```
```
• CNS
o Learning disability
Usually mild
30-50%
o Large head
```
74
what is the diagnostic criteria for neurofibromatosis
• Diagnostic criteria
o Two or more of
≥ 6 café au lait spots
• ≥ 1.5 cm in postpubertal individuals
• ≥ 0.5 cm in prepubertal individuals
≥ 2 neurofibromata or ≥ 1 plexiform neurofibroma
Freckling in axilla, neck or groin
Optic glioma
≥ 2 lisch nodules
Distinctive bony lesion
• Dysplasia of sphenoid bone or dysplasia of long bone cortex
First degree relative with NF1
* Variability in phenotype makes reproductive decision making difficult
* Value of screening - differences between different healthcare systems
* Mutation analysis of limited value
75
describe Von Hippel Lindau disease
* Affects 1 in 35,000 individuals
* Penetrance high
• Associated with a wide variety of tumours
o retinal angiomas (60%)
o haemangioblastomas (cerebellar 60%, spinal 25% and brainstem 18%)
o renal cell carcinoma (28%)
o phaeochromocytoma (15%)
* vHL protein suppresses tumour growth and downregulates angiogenic factors.
* ~ 90% individuals with clear diagnosis of vHL will have mutation identified
• Screening
o Ages 5-18
Eye/retinal examination
24 hour urine collection for catecholamines
```
o Ages 18-65
Eye/retinal examination
Physical examination
24 hour urine collection for catecholamines
MRI of abdomen
```
MRI of brain and spine (2-3 yearly)
76
describe Familial adenomatous polyposis
```
1 in 10,000
• polyps develop during second decade
• colonic malignancies third decade
• Associated features
o CHRPE (Congenital Hypertrophy of the Retinal Pigment Epithelium)
o Desmoid tumours
o Osteomas
```
APC (adenomatous polyposis coli) mutations
• Majority truncating mutations
• attenuated FAP
77
why are twin studies useful
monozygous and dizygous
If the co twin is affected as well then they are concordant
If not they are discordant
Usually same sex twins are used
78
describe genetic testing in complex genetic disorders
* Genetic association studies
* Everyone has millions of SNIPs which are different to the reference genome
* Sequencing people with arrays with the disease you are interested in and those without should give an indication of SNIPs which contribute to the disease
79
negatives of presymptomatic testing
* no medical benefit
* side-effects unknown
* many people request test to confirm they do not have the condition
* insurance/mortgage problems
80
positives of presymptomatic testing
* removes uncertainty
* clarifies reproductive risks
* career/lifestyle choices
81
describe presymptomatic testing for non-genetic reasons
* performed only in specialist units
* restricted to adults
* obligate carriers are a problem
* may be done for reproductive reasons alone
* should become rarer
82
describe presymptomatic testing
• does not always require DNA test
– clinical examination
– investigations
• if done for medical reasons
– should result in a preventative intervention
– family implications need to be considered
• testing of children is appropriate if intervention starts in childhood
83
what are the requirements for screening for a condition
* Well-defined disorder
* Known incidence
* Significant morbidity or mortality
* Effective treatment available
* Period before onset where intervention improves outcome
* Ethical, safe, simple and robust screening test
* Cost-effective
84
causes of developmental disorders
```
40% diagnostic rate
78% de novo
12% recessive
10% inherited (het/hemi)
plus 4% “uncertain”
```
85
what is an issue with whole genome sequencing?
the possibility of identifying possibly causative variants in disease associated genes that are not related to the condition under investigation - incidental findings
86
describe genomic imprinting
non mendelian
• Defined as differences in gene expression depending on whether the gene was paternally or maternally inherited
• Specific chromosomal regions contain imprinted genes
• Such regions usually contain maternally and paternally imprinted genes
• Normal cellular process
• Leads to functional hemizygosity
• Accounts for only a small number of genes
• Many developmental genes are imprinted
• Disruption of imprinting is implicated in several well known genetic disorders and many cancers
Angelmans and prader-willi syndromes are the same deletion on chromosome 15 but in angelmans the chromosome in derived from the mother and prader-willi it is derived from the father
Loss of heterozygosity
87
what causes disruption of genomic imprinting
* Parent specific chromosome deletion
* Methylation abnormalities
* Uniparental disomy
* Gene mutations
88
what cancers can genomic imprinting lead to
```
Wilm’s tumour
Neuroblastoma
Acute Myeloblastic Leukaemia
Rhabdomyosarcoma
Osteo-sarcoma
```
89
describe mitochondrial DNA
• 16,559 base pairs
• Many copies in a cell, dependent on energy requirement of cell/tissue
• Contains important genes for mitochondrial metabolic
pathways and ribosomal RNAs
• Maternally inherited
• High rate of mutations
– Point mutations and deletions occur
• Double stranded
• Ring structure
• No Introns
• Genes are tightly packed together
• Few or no non-coding nucleotides between genes
• Approx 92% of the mitochondrial genome has
coding function.
90
what can mitochondrial mutations lead to?
```
- Pearson (Marrow-Pancreas) Syndrome
– Kearns Sayre Syndrome
– Myopathy
– Ataxia
– Cardiomyopathy
– Leighs encephalopathy
– Liebers Hereditary optic neuropathy
```
91
what is heteroplasmy
Different daughter cells have different proportions of mutant mitochondria
92
what does severity and nature of phenotype of mitochondrial conditions depend on
– type of tissue involved
– proportion of mitochondria carrying a mutation
– type of mutation
93
what is the inheritance pattern of mitochondrial disorders
Maternal inheritance only if affected gene is from mitochondrial DNA
• Mitochondrial DNA does not code for all mitochondrial protein
• If abnormal mitochondrial protein is coded from genomic DNA then genetic disorders follow mendelian patterns of inheritance
94
describe dynamic mutations/triplet repeat expansions
Mutations are evolving
• Not stably inherited
• Mutations are (usually) increasing in size with successive generations
– But can also contract in size
• Has a threshold effect
• Exhibit a relationship between severity and copy number
– Explains the clinical phenomenon of Anticipation
• More severe in succeeding generations
most common are triplet repeats
Expansion of repeats usually has gender bias
– e.g. HD – expansion when transmitted from paternal line
– Fragile X – expansion when transmitted from maternal line
• Accounts for over 40 neurological, neuromuscular and neurodegenerative disorder
95
describe mosaicism
* An autosomal dominant mutation can arise during somatic cell division, after formation of the zygote. Only a proportion of cells in the body will therefore carry a mutation, and the indivdual may show no features of disease, the features may be milder, or the features may affect only one body area. The mutation may only be present in gonadal tissue.
* If a child is the first in a family to be affected with a dominant disease, this may be because of a new mutation or there may be gonadal mosaicism in the parent. This gives a higher recurrence risk than expected.
* Gonadal mosaicism is more common in specific diseases, such as osteogenesis imperfecta and duchenne muscular dystrophy. Often the genes involved are larger, and presumably therefore, more prone to somatic mutation.
96
where can trinucleotide repeats be
* In the untranslated region of gene, for example the (CCG)n repeat in fragile X, or the (CTG)n repeat in myotonic dystrophy.
* In the coding sequence of a gene, for example the (CAG)n repeats in Huntingtons disease and the spino-cerebellar ataxias.
97
describe digenic Inheritance
* First came to light in patients with Sensorineural deafness
* >100 genes involved
* Usually conform to mendelian patterns of inheritance
• However a proportion of patients with deafness, were double heterozygotes for known deafness genes
– ie no hearing deficit were found in patients who were only carriers of a mutation in a single locus but deafness occurred where patients were carriers of mutations in 2 gene loci
98
describe contiguous gene deletion syndromes
“A syndrome caused by a microdeletion that spans two or more genes tandemly positioned along a chromosome
```
Well known ones:
o Williams-Beuren syndrome 7q11.23- failed homologous non-allelic recombination
o DiGeorge syndrome 22q11.2
o Wolf-Hirschhorn syndrome 4p16.3
o Smith-Magenis syndrome 17p11.2
```
99
how do we correlate genotype and phenotype
* Is the clinical manifestations due to the genes which have been deleted
* If so can we attribute particular phenotype to the particular genes which has been deleted
* Or is the syndrome due to just one of the genes that has been deleted
100
describe subtelomeric chromosomal rearrangements
o Majority of translocations involve chromosome ends (shared telomere-associated repeats)
o Gene rich adjacent regions (rearrangements likely to have phenotypic consequences)
• Moderate-severe mental retardation
o for sporadic cases (7%)
o for familial cases (25%)
101
describe somatic mosaicism
• All cells suffer mutations as they divide
o At meiosis and at mitosis
o Approximately 10-6 per gene per cell division
• Repair Mechanisms Exist
o Can give rise to reversion
• Given the numbers of cells in the body
o everybody will have some cells which has a mutation of some sort
102
when might somatic mosaicism become clinical important
* If mutant cells has tendency to grow and replace normal cells (cancer cells)
* If the mutation arose early in embryonic development, so becomes a large proportion of the whole body
* If the mutation occurred in the germ line
Some conditions where a pure condition would be lethal but a mosaic present with a milder phenotype and can survive
103
describe Gonadal Mosaicism
• Commoner in some diseases
– Duchenne Muscular Dystrophy
– Osteogenesis Imperfecta
• Can offer pre-natal diagnosis for a second child, even when parents are unaffected (if a mutation is identified)
• Causes recurrence risk for fatal dominant conditions
104
what are dicentromeric chromosomes caused by
robertsonian translocations
105
the highly conserved bases in the 3' splice site are..
AG rich
106
the highly conserved bases in the 5' splice site are..
GU rich
107
During splicing which sites are recognized by the splicosome?
5’ splice site or the donor, the branch point site and the 3’ splice site known as the acceptor.
