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
