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EMS > Lecture 13: Single-gene pathology 1 > Flashcards

Lecture 13: Single-gene pathology 1 Flashcards

1
Q

What are single gene disorders?

A

Genetic conditions caused by pathogenic variants (mutations) in a single gene
Simple genetic aetiology
Straightforward inheritance patterns

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2
Q

Challege to the over simplified tern ‘Simple gene disorders’?

A

Allelic heterogeneity
Locus heterogeneity

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3
Q

What can different pathogenic variants in a single gene lead to? (Allelic heterogeneity)

A

Multiple different phenotypes

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4
Q

Which is compatible with life, Achondroplasia or thanatophoric dysplasia?

A

Achondroplasia (Compatible with life)
thanatophoric dysplasia (lethal)

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5
Q

What does genotype allow for mothers of unborn children?

A

GENOTYPE ALLOWS INFORMED DECISION MAKING IN PREGNANCY

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6
Q

What is locus heterogeneity?

A

Pathogenic variants in different genes that lead to one phenotype.

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7
Q

Give an example of locus heterogeneity?

A

Retinitis pigmentosa
Non-syndromic: > 80 genes
Syndromic: many more!

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8
Q

Characteristics of single gene testing?

A

Slow
Expensive

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9
Q

What type of testing are we moving towards?

A

Genomic testing

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10
Q

Types of genomic testing?

A

Sequence many genes
Gene panel
Clinical exome
Whole exome
Whole genome

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11
Q

What are other syndromes showing locus heterogeneity?

A

Lynch Syndrome
Tuberous sclerosis
Noonan syndrome

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12
Q

What is phenotypic variability?

A

Different individuals with the same single gene disorder that leads to Different phenotypic features of different severities

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13
Q

Give an example of Phenotypic variability?

A

Osteogenesis imperfecta
- Lethal
- Moderate
- Mild

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14
Q

What problems can abnormal chromosomes cause?

A

Chromosome number
Chromosome structure
Missing or extra chromosomal material (copy number variation)

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15
Q

What problems can abnormal genes cause?

A

Nonsense
Frameshift
Missense
Splicing
Single or multi-exon deletions/insertions
Repeat expansions

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16
Q

What are point mutations?

A

= a mutation that affects a single nucleotide

17
Q

What do point mutations include?

A

the substitution of one base for another
insertions or deletions of a single base pair

18
Q

What is the most common type of mutation?

A

Point mutation

19
Q

What are polymorphisms?

A

Common single nucleotide changes

20
Q

What are missense variants?

A

DNA change → codon alteration → incorporation of different amino acid at that position

21
Q

What do missense variants cause?

A

Substitution -Effect on protein depends on the degree of difference between the reference and substituted amino acids

22
Q

What is conservative missense?

A

amino acid substitution within same group

23
Q

What is non- conservative missense?

A

amino acid substitution to one in a different group

24
Q

How can we predict the pathogenicity of missense variants?

A

Assesses the effect of amino acid substitutions on the structure or function of a protein without conducting functional studies

25
Q

Give examples of predictive software?

A

CADD (Combined Annotation Dependent Depletion)
PolyPhen II
SIFT

26
Q

What are the most problematic mutations?

A
  1. Nonsense
  2. Frameshift
    3.Canonical 1 or 2 splice site variants
  3. Loss of start codon
  4. Single exon or multiexon deletion
27
Q

How many reading frames are there?

A

3 possible reading frames

28
Q

What determines the reading frame?

A

Translation starts at the start codon
= ATG
Codes for METHIONINE

29
Q

What are frameshift mutations?

A

= insertion or deletion of nucleotide(s) in number not divisible by three

30
Q

What happens during a frameshift mutation?

A

1.Leads to disruption of the reading frame
2.Subsequent sequence will be read incorrectly
3. Eventually leads to reading of a premature stop codon and truncation of the protein

31
Q

What are Canonical splicing variants?

A

= variants that occurs at the boundary of an exon and an intron (canonical splice site) and impact splicing

32
Q

How does canonical splice sites cause damage?

A

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

33
Q

What is gain of function variants?

A

Where the mutation leading to the normal function not to be working, however the gene has a new function that is carried out

34
Q

is gain of functions dominant or recessive?

A

Almost always dominant

35
Q

What is a loss of function variants?

A

Variants associated with reduced or abolished gene function

36
Q

Is loss of functions usually dominant or recessive?

A

Frequently RECESSIVE –1 normal copy produces enough functional protein to allow gene to work

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