Lecture 13: Single-gene pathology 1 Flashcards
What are single gene disorders?
Genetic conditions caused by pathogenic variants (mutations) in a single gene
Simple genetic aetiology
Straightforward inheritance patterns
Challege to the over simplified tern ‘Simple gene disorders’?
Allelic heterogeneity
Locus heterogeneity
What can different pathogenic variants in a single gene lead to? (Allelic heterogeneity)
Multiple different phenotypes
Which is compatible with life, Achondroplasia or thanatophoric dysplasia?
Achondroplasia (Compatible with life)
thanatophoric dysplasia (lethal)
What does genotype allow for mothers of unborn children?
GENOTYPE ALLOWS INFORMED DECISION MAKING IN PREGNANCY
What is locus heterogeneity?
Pathogenic variants in different genes that lead to one phenotype.
Give an example of locus heterogeneity?
Retinitis pigmentosa
Non-syndromic: > 80 genes
Syndromic: many more!
Characteristics of single gene testing?
Slow
Expensive
What type of testing are we moving towards?
Genomic testing
Types of genomic testing?
Sequence many genes
Gene panel
Clinical exome
Whole exome
Whole genome
What are other syndromes showing locus heterogeneity?
Lynch Syndrome
Tuberous sclerosis
Noonan syndrome
What is phenotypic variability?
Different individuals with the same single gene disorder that leads to Different phenotypic features of different severities
Give an example of Phenotypic variability?
Osteogenesis imperfecta
- Lethal
- Moderate
- Mild
What problems can abnormal chromosomes cause?
Chromosome number
Chromosome structure
Missing or extra chromosomal material (copy number variation)
What problems can abnormal genes cause?
Nonsense
Frameshift
Missense
Splicing
Single or multi-exon deletions/insertions
Repeat expansions
What are point mutations?
= a mutation that affects a single nucleotide
What do point mutations include?
the substitution of one base for another
insertions or deletions of a single base pair
What is the most common type of mutation?
Point mutation
What are polymorphisms?
Common single nucleotide changes
What are missense variants?
DNA change → codon alteration → incorporation of different amino acid at that position
What do missense variants cause?
Substitution -Effect on protein depends on the degree of difference between the reference and substituted amino acids
What is conservative missense?
amino acid substitution within same group
What is non- conservative missense?
amino acid substitution to one in a different group
How can we predict the pathogenicity of missense variants?
Assesses the effect of amino acid substitutions on the structure or function of a protein without conducting functional studies
Give examples of predictive software?
CADD (Combined Annotation Dependent Depletion)
PolyPhen II
SIFT
What are the most problematic mutations?
- Nonsense
- Frameshift
3.Canonical 1 or 2 splice site variants - Loss of start codon
- Single exon or multiexon deletion
How many reading frames are there?
3 possible reading frames
What determines the reading frame?
Translation starts at the start codon
= ATG
Codes for METHIONINE
What are frameshift mutations?
= insertion or deletion of nucleotide(s) in number not divisible by three
What happens during a frameshift mutation?
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
What are Canonical splicing variants?
= variants that occurs at the boundary of an exon and an intron (canonical splice site) and impact splicing
How does canonical splice sites cause damage?
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
What is gain of function variants?
Where the mutation leading to the normal function not to be working, however the gene has a new function that is carried out
is gain of functions dominant or recessive?
Almost always dominant
What is a loss of function variants?
Variants associated with reduced or abolished gene function
Is loss of functions usually dominant or recessive?
Frequently RECESSIVE –1 normal copy produces enough functional protein to allow gene to work
