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
