Lecture 14: Single gene pathology 2 Flashcards
Questions to ask: Evidence of variants?
What kind of variant is it? How damaging is that?
Is the variant rare enough to cause a rare disease?
Is there anything published about my variant?
Is the variant conserved throughout evolution?
How common is my variant?
What is counted as a rare disease?
discount anything > 1% in healthy reference population
What are the different outcomes if reference base/amino acid conserved across species, throughout evolution?
yes = Suggests its functionally important
no = likely to do harm
What are the different classified variants into 5 categories?
Class 1: Benign
Class 2: Likely benign
Class 3: Variant of uncertain significance
Class 4: Likely pathogenic
Class 5: Pathogenic
What are the criteria for the classification of variants?
Formula for variant classification according to amount and strength of variant evidence.
What is contained in the average human genome?
3 billion DNA bases
20,000 genes
4-5 million variants
What types of variants are found in the average human genome?
3.5 million single nucleotide variants
~ 350,000 small insertions/deletions
~2000-2500 structural variants
(~ 1000 chromosomal insertions/deletions (copy number variants)
~100 genuine loss of function variants
50-100 variants previously described as ‘disease causing’
~ 50 new (de novo) variants)
What is the ideals of traditional genetics?
Sequence a gene based on clinical suspicion of a single gene disorder
Pros and cons of traditional genetics?
Sequence multiple suspicious genes sequentially
- expensive and time consuming
Sequence a gene based on clinical suspicion of a single gene disorder
– may not be correct
- may be more than one causative gene
Ideals of modern genomics?
Sequence hundreds-thousands of genes at once
Analyse relevant data
What are the challenges of modern genomic diagnostics?
1.Find the exact genetic change to explain a patient’s features (phenotype)
2. Finding undesired incidental findings
3.Be able to interpret the changes we find to distinguish normal individual variation from disease-causing variation
What is DNA instability?
= the acquisition of new DNA variants between one generation and the next
Types of DNA instability?
Germline: source of individual variation and new disease variants
Somatic: driving force for cancer
What does DNA instability include?
Point mutations
Chromosomal rearrangements
Aneuploidy
What are the causes of DNA instability?
Fragile sites including repetitive DNA sequences
DNA replication defects
What percentages of the genome sequences is repetitive?
50-70%
Types of repetitive sequences?
Simple tandem repeats
Interspersed repeats - aka transposable elements (TE’s)
= JUMPING genes
How are TE’s Mutagenic?
Insertion into a functional gene can disable it
An unrepaired gap in a gene can damage it
Repetitive sequence can hinder precisechromosomalpairing duringmitosisandmeiosis → unequalcrossing over → generation of DELETIONS and DUPLICATIONS
What are the types of mutations (Duchenne Muscular Dystrophy)
Large deletions - One or more exons are missing from the dystrophin gene
Large duplications - One or more exons have extra copies in the dystrophin gene
Other changes - Small changes, such as tiny deletions or changes in a single letter in the DNA
How do we find the causative variant?
Array CGH
Sequence analysis
Deletion/duplication analysis
What are triple repeat disorders?
Triplet repeats = sequences of 3 nucleotides that are repeated multiple times
Triple repeat disorders characteristics?
Healthy people: variable number
Threshold beyond which high number causes disease
> 50 disorders described
What is Huntington’s Disease?
= Dominant progressive neurodegenerative disorder
Symptoms of Huntington’s disease?
Motor: involuntary movement
Cognitive: dementia
Psychiatric disturbances
What is anticipation?
When mutant allele inherited paternally
Bigger expansions through generations
Earlier age of onset
