10 - Evaluating Genomic Variants Flashcards
Purpose of genetic testing
- Accurate molecular diagnosis
- Disease prognosis
- Cascade screening (family members)
- Screening
- Monitoring
Pathogenic variant
Capable of causing disease
Benign variant
Not harmful in effect
Mutation
ONLY pathogenic/disease causing variants
Polymorphism
Variant that is common in a normal population
Targeted detection of diagnostic variant
- Focuses on a specific gene location, size or region, and/or type of variant
- Diseases associated
Why are these restrictions of detection chosen
- Ease of interpretation
- Proven clinical utility
- Limited resources
Are all variants in an individuals DNA disease causing
Nah
Steps in determining variant pathogenicity
- Determine if variant is known or novel (via disease associated or normal variant databases, literature)
- Seen locally?
- Critically appraise the evidence
Nonsense and frameshift mutation pathogenicity
Assumed disease causing, provided that a loss of function/dominant negative effect is supported
Synonymous variants and mutations not near genes pathogenicity
Assumed to be non disease causing
Missense mutation pathogenicity
may have no effect, loss of function or gain of function
Mutation
Change in DNA sequence that is probably disease causing
Variant
Change in DNA sequence
Mod of inheritance
Dominant, recessive, X linked, autosomal
Alleles/zygosity
Heterozygous, homozygous, compound heterozygous, hemizygous
Genomic location
Coding, promoter/regulatory, splice site
Molecular change
- Substitution (synonymous, missense, nonsense)
- Deletion/insertion
Functional effect
Loss/gain of function
Homozygous
Same mutation present on both alleles
Heterozygous
Mutation present on one allele only
Compound heterozygous
Two different mutations present, one on each allele
Hemizygous
On sex chromosomes, A mutation on one allele, and the other allele is absent
De novo variant
Mutation found in child but not parents and is usually dominant disease
Variants in trans
variants located on different copies of a homologous chromosome
Filtering
- Remove variants observed frequently in populations
- Remove synonymous variants
- Remove variants not in coding regions or at splice sites
- Remove variants predicted to have little effect on protein function
Amino acids that are highly conserved across species
Variant in these regions would be of high concern
Functional data
- Functional studies focus on the dynamic effects of changes at the DNA level on gene transcription, translation and protein-protein interactions.
- Range from cDNA studies to complex animal models
Goal of functional data studies
To understand the relationship between genetic variants and phenotype
Variant hot spots
Disease causing variants have nonrandom distribution, occurring in specific functional domains
