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Yr 2 - EMS > Single Gene Pathology > Flashcards

Single Gene Pathology Flashcards

1
Q

What is a single gene disorder? What is the other name for it?

A

When a certain gene is known to cause a disease Also referred to as a Mendelian disorder.

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2
Q

What is a ‘locus’?

A

The specific physical location of a gene or other DNA sequence on a chromosome (like a genetic street address)

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3
Q

What is allelic heterogeneity?

A

The presence of different variants at a single gene locus (i.e. in a single gene) that cause the same or similar phenotypic expressions of a disease or condition.

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4
Q

What is locus heterogeneity?

A

Opposite to allelic heterogeneity

Pathogenic variants in different genes (i.e. mutations at multiple genomic loci) are capable of producing the same phenotype

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5
Q

What is ‘retinitis pigmentosa’?

A

A condition that causes damage to the light-sensitive cells of the retina

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6
Q

Is retinitis pigmentosa an example of allelic or locus heterogeneity? Why?

A

Locus heterogeneity There have been over 60 genes identified whose mutations independently cause retinitis pigmentosa I.e. mutations in different genes but same phenotype

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7
Q

What are the 2 bases for genetic variation?

A

Abnormal chromosomes Abnormal genes

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8
Q

What are the potential problems with chromosomes?

A
  1. Chromosome number (missing or extra chromosomes e.g. aneuploidy) 2. Chromosome structure (translocations) 3. Missing or extra chromosomal material (deletions or duplications) –> CNV
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9
Q

What is CNV?

A

When the number of copies of a particular gene varies from one individual to the next due to the genome experiencing gains and losses of genetic material.

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10
Q

What are the potential problems with genes?

A
  1. Point mutations 2. Single or multi-exon deletions/insertions 3. Repeat expansions
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11
Q

What is a point mutation?

A

A mutation that affects a SINGLE nucleotide (A, T, C or G) Includes: - substitution of one base for another - insertions or deletions of a single base pair

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12
Q

How common are point mutations?

A

By far the most common type of mutation –> most common cause of disease

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13
Q

Point mutation example

A

Here, the G on the top stranded has mutated and been changed to a T

The C on the complementary strand is therefore changed to an A

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14
Q

Brief overview of transcription and translation

A

DNA transcribed to RNA mRNA triplet code ‘read’ by ribosome –> 3 letters of mRNA = a codon Encoded protein translated

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15
Q

Can there be multiple codons for one amino acid?

A

Yes, there are multiple codons for each amino acid

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16
Q

Why might there be no effect on proteins/person even if there is a variant/mutation?

A

Most variants have no effect!

The mutation may not alter the protein sequence –> this is a SYNONYMOUS mutation

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17
Q

What is a missense mutation?

A

This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene –> this is a nonsynonymous mutation as the amino acid sequence is changed

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18
Q

How does a missense mutation and a point mutation differ?

A

A point mutation is where you change one base in the DNA to another. A missense mutation occurs when that point mutation causes a different amino acid to be placed from that codon.

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19
Q

Synonymous vs nonsynonymous mutations?

A

Synonymous - amino acid sequence is not altered

Nonsynonymous - amino acid sequence is altered

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20
Q

If a mutation does cause a change in amino acid sequence, what are the potential effects?

A
  1. No effect
  2. Little effect
  3. Signifiant damaging effect
  4. Null effect
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21
Q

What is ‘null effect’?

A

A complete absence of the gene’s protein product - mutation caused a lack of production of the associated gene product OR a product that doesn’t function properly

A null allele is a nonfunctional allele (a variant of a gene) caused by a genetic mutation.

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22
Q

Examples of different point mutations

Remember U replaces T in mRNA

A

Mutation 1: UAC and UAU both code for Tyrosine so there will be no change in amino acid –> synonymous

Mutation 2: AAC codes for Asparagine so there has been a change in amino acid –> missense change

Mutation 3: UAG is a stop codon –> will stop protein from being formed properly so will have negative impact on protein

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23
Q

What will be the resulting proteins here? How will they be affected?

A
  1. Normal
  2. Normal
  3. Faulty
  4. Short
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24
Q

What type of mutation is 1, 2, 3, 4?

A
  1. Wild type
  2. Synonymous - no change in amino acid
  3. Missense - change in amino acid due to change in a single base pair
  4. Nonsense - substitution of a single base pair that leads to a stop codon where previously there was a codon specifying an amino acid
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25
What is a missense mutation?
Change of a single base pair --\> codon altered --\> substitution of a different amino acid in the resulting protein This amino acid substitution may have no effect, or it may render the protein nonfunctional.
26
What does the effect on the protein of a missense mutation depend on?
The effect depends on degree of difference between the reference and substituted amino acid
27
What are the 2 types of missense mutations?
1. Conservative 2. Non-conservative
28
What is a conservative missense mutation?
Amino acids have side chains called R groups which can be grouped into different categories according to their structure and function. A conservative missense is an amino acid substitution within the same R group
29
What is a non-conservative missense mutation?
Amino acid substitution to one in a different group --\> much more likely to do harm to the protein due to different structure/function
30
What type of missense mutation would an alanine to a leucine be?
Conservative as both fall within aliphatic group (amino acid with hydrophobic side chain)
31
What type of missense mutation would an alanine to glutamic acid be?
Non-conservative - change from hydrophobic side chain group (aliphatic) to electrically charged side chain group (acidic)
32
Examples of *'in silico'* software used to assess the effect of amino acid substitutions?
* CADD (Combined Annotation Dependent Depletion) * Polyphen II * SIFT
33
What types of mutations can cause null variants?
1. Nonsense --\> normal amino acid changed to stop codon 2. Frameshift 3. Canonical +/- 1 or 2 splice sit variants 4. Loss of start codon 5. Single exon or multiexon deletion
34
What is the 'reading frame' of mRNA?
* A way of dividing the sequence of nucleotides in a nucleic acid (DNA or RNA) molecule into a set of consecutive, non-overlapping triplets. * The mRNA is single-stranded and therefore only contains **three possible reading frames**, of which only one is translated. * The codons of the mRNA reading frame are translated in the 5′→3′ direction into amino acids by a ribosome to produce a polypeptide chain.
35
Example mRNA: CAUCGCGAUUGACGGGUUUACAAC What are the 3 possible reading frames?
1. CAU | CGC | GAU | UGA | CGG | GUU | UAC | AAC 2. C | AUC |GCG |AUU |GAC |GGG |UUU |ACA | AC… 3. CA |UCG |CGA |UUG |ACG |GGU |UUA |CAA | C… Each would produce a completely different chain of amino acids!
36
How can you determine the reading frame?
Translation starts at the **start codon** which is ATG --\> codes for **methionine** The most common start codon is AUG (i.e., ATG in the corresponding DNA sequence).
37
What is a frameshift mutation?
This type of mutation occurs when the **addition or loss of DNA bases** changes a **gene's reading frame** --\> insertion or deletion of nucleotide(s) in number **not divisible by 3** Result: The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations. Eventually leads to reading of a premature stop codon.
38
Example: **_Wild Type_** DNA: ATG GAT TTG CAC mRNA: AUG GAU UUG CAC Protein: Met-Asp-Leu-His **_Frameshift Mutation_** --\> Extra T has been inserted DNA: ATG **T**GA TTT GCA C mRNA: AUG UGA UUU GCA C Protein: Met-STOP (UGA is a stop codon)
39
What is 'wild type' DNA?
The allele that encodes the phenotype most common in a particular natural population is known as the wild type allele. Any form of that allele other than the wild type is known as a mutant form of that allele.
40
What is RNA splicing?
A form of RNA processing in which a newly made pre-mRNA transcript is transformed into mRNA. During splicing, introns are removed and exons are joined together. Splicing takes place within the nucleus either during or immediately after transcription.
41
What are canonical splicing variants?
Variants that occur at the boundary of an exon and an intron (canonical splice site) and impact splicing N.B. a canonical splice site is the boundary of an exon and an intron
42
Where must the nucleotide be altered in a canonical splice site to have an effect?
Alteration of the first or second nucleotide into the intron has a damaging effect on splicing and will lead to translation of a damaged protein I.e. -1/-2 on the 5' acceptor end OR +1/+2 on the 3' donor end
43
Describing genetic variants:
Most common you'll see is 'c.' --\> this refers to the first nucleotide of the translation start codon of the coding DNA reference sequence
44
What is a gain-of-function mutation?
A type of mutation in which the altered gene product possesses **a new molecular function** or a n**ew pattern of gene expression**.
45
Are gain-of-function variants dominant or recessive?
Almost always **dominant**
46
What type of mutation is 'achondroplasia' caused by?
Gain of function mutation
47
What is achondroplasia?
A disorder of bone growth that prevents the changing of cartilage (particularly in the long bones of the arms and legs) to bone. It is characterized by dwarfism, limited range of motion at the elbows, large head size (macrocephaly), small fingers, and normal intelligence.
48
What is achondroplasia caused by?
A gene mutation in the FGFR3 gene --\> FGFR3:c.1138G\>C (p.Gly380Arg) This increases the activity of FGFR3, severely limiting bone growth
49
What is the normal function of FGFR3?
Slows down the formation of bone by inhibiting the proliferation of chondrocytes
50
What nomenclature is used to denote a change when one nucleotide is replaced by another? i.e. substitution
\> E.g. g.1318G\>T
51
What does g. stand for?
The first nucleotide of the genomic reference sequence
52
What nomenclature is used to denote a deletion?
Del E.g. g.3661\_3706del
53
What is a loss of function variant?
Variants associated with reduced or abolished gene function
54
Are loss of function mutations recessive or dominant?
Frequently **recessive** - 1 normal copy produces enough functional protein to allow gene to work E.g. cystic fibrosis, beta thalassaemia
55
Why are loss of function variants normally recessive
1 normal copy produces enough functional protein to allow the gene to work
56
Things to consider when assessing variants
1. What type of variant is it? 2. How common is variant? 3. Clinical features and inheritance pattern? 4. Is the variant conserved throughout evolution? If so, is it functionally important?
57
When is a disease considered rare?
If \< 1% in healthy reference population
58
What is ACMG pathogenicity classification?
Formula for variant classification according the **amount and strength** of variant evidence
59
What are the 5 categories used for classification in ACMG?
Class 1: Benign Class 2: Likely benign Class 3: Variant of uncertain significance Class 4: Likely pathogenic Class 5: Pathogenic
60
What is 'aetiolgoy'?
Cause of a disease
61
What is 'pathogenesis'?
Mechanism causing the disease
62
What is 'sequelae'?
Secondary, systemic or remote consequences of a disease
63
What is 'prognosis'?
Anticipated course of the disease in terms of cure, remission, or fate of the patient
64
What is 'epidemiology'?
The incidence, prevalnce and population distribution of a disease
65
Summary of tools and databases:
* Genes and phenotypes: OMIM https://www.omim.org * Reference human genome: UCSC and Ensembl https://genome.ucsc.edu, https://www.ensembl.org/index.html * Variant pathogenicity: ClinVar https://www.ncbi.nlm.nih.gov/clinvar/ * Variant frequency: gnoMAD https://gnomad.broadinstitute.org * Variant effect predictor: VEP https://www.ensembl.org/info/docs/tools/vep/index.html
66
Example scenario: * 7-year-old boy seen in genetics clinic * Intellectual disability, global developmental delay, coloboma, conductive hearing loss, VSD, undescended testes, short stature * No affected family members * Clinical exome identifies this variant: * Chr 8: 60855993 C \> T * →Run through Ensembl VEP
VEP results: * Missense variant * Causes arginine to cysteine * Gene CHD7 * Predicted pathogenic by *in silico* tools * Very rare * Published on PubMed Don't need to learn this, just an example of using VEP
67
What is DNA instability?
The acquisition of new DNA variants between one generation and the next. Includes: * Point mutations * Chromosomal rearrangements * Aneuploidy
68
What are germline variants responsible for?
Source of individual variation and new disease variants
69
What are somatic variants responsible for?
Driving force for cancer
70
What are the causes of DNA instability?
* Fragile sites including **repetitive DNA sequences** * DNA replication defects
71
How much of the human genome is made up of repetitve sequences? What are the different types?
50-70% * Simple tandem repeats (stretches of DNA that are repeated back to back) * Interspersed repeats - aka transposable elements (TE's) * May function as JUMPING genes * Found all over genome in different places
72
What is a TE / jumping gene?
A DNA sequence that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transposition often results in duplication of the same genetic material.
73
How can TE's be mutagenic?
* Jumping gene can move into a functional gene and disable it * Can jump out of a functional gene and an unrepaired gap can damage it * Repetitive sequence can hinder precise chromosomal pairing during mitosis and meiosis --\> unequal crossing over --\> generation of **deletions and duplications**
74
What types of mutations can Duchenne muscular dystrophy be due to?
1. Large deletions (72%) 2. Large duplications (7%) 3. Other changes (20%) (e.g. tiny deletions or changes in a single letter in the instructions)
75
How can large deletions cause Duchenne?
One or more exons are missing from the dystrophin gene - stop the remaining exons fitting together properly
76
How can large duplications cause Duchenne?
One or more exons have extra copies in the dystrophin gene
77
What genetic tests should be done for Duchenne to make sure you cover all the causative variants?
1. Array CGH --\> to look for big deletions and duplications 2. Sequence analysis 3. Deletion/duplication analysis
78
Cause of Williams syndrome?
A big deletion on chromosome 7
79
Cause of Di George syndrome?
Big deletion on chromosome 22
80
What are triplet repeats disorders?
Sequences of 3 nucleotides that are repeated back to back multiple times --\> falls into the tandem repeat category * Healthy people have a variable number of triplet repeats * Beyond this threshold number, it can cause disease (i.e. high numbers of triplet repeats can cause disease)
81
What is the repeat sequence for Huntington's?
Repeat of CAG within the Huntington gene Repeat sequence: CAG Gene: HTT Normal range: 6-35 Disease range: 36-250
82
Repeat sequence for Fragile X syndrome?
CGG on the FMR1 gene
83
What is Huntington's disease?
Dominant progressive neurodegenerative disorder * Motor: involutary movement * Cognitive: demetia * Psychiatric disturbances
84
Does Huntington's show anticipation?
When mutant allele is inherited **paternally** it shows anticipation (number of repeats can get bigger and bigger as moves through generations) --\> associated with earlier age of onset
85
Difference between allelic and locus heterogeneity
86
Tuberous sclerosis can be caused by pathogenic variants in two genes: TSC1 and TSC2. Is this an example of allelic or locus heterogeneity?
Locus heterogeneity
87
Different variants in the USH2A gene can cause isolated retinitis pigmentosa, or a deaf-blindness disorder called Usher's syndrome. Is this an example of allelic or locus heterogeneity?
Allelic heterogeneity - 1 gene causing multiple different phenotypes
88
Which of these variants is most likely to be pathogenic? 1. Conservative missense 2. Synonymous 3. Frameshift
Frameshift --\> is a **null variant** Leads to a premature termination of protein
89
Why is a conservative missense mutation less likely to be pathogenic?
Change from one amino acid to another but falls within the same category (similar side chain), less likely to be harmful
90
Which would be the most useful test to diagnose 2 siblings with retinitis pigmentosa? 1. Chromsome test 2. Single gene test: USH2A 3. Clinical exome with analysis of genes causative of retinitis pigmentosa
* Clincal exome with analysis of genes causative of retinitis pigmentosa --\> don't have a clear gene candidate just based on family history and phenotype alone * Retinitis pigmentosa can be caused by mutations in over 60 genes * Chromosome test not helpful as retina pigmentosa is a Mendelian disorder --\> alterations in **one gene**

Yr 2 - EMS (60 decks)

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