Genetic variants and classification Flashcards
Normal gene features
23 pairs of chromosmes
All separate from each other
All gees present
Nucleic acid sequence typical
2 copies of each autosomal chromosome
What is aneuploidy
Too many or too few chromosomes eg monosomy = missing one, trisomy - one extra
Common aneuplodies
Trisomy 21 (downs), 13, 18, sex - eg 45 X0 (Turners), 45XXX (kleinfelters)
What is translocation balanced vs unbalaned
One chromosome stuck onto another = translocation
Balanced - no missing or extra -> normal
Unbalanced -> phenotypic effect
What can detect a balanced translocation
Karyotype
What is a copy number variant
Large chunks of DNA either duplicated or deleted
How detect copy number variant
SNP array
What type of genetic variation is di george syndrome
Copy number variant
22q11.2 deletion -> 78 genes only one copy
What are introns
Non protein coding DNA between exons
Regulatory functions, splice sites
What are exons
Code for proteins
Cause majority of genetic disease
Introns spliced out
What is a synonymous subsitiution
Single nucleotide change - doesnt change waht aa coded for
No change in aa sequene
Low likelihood of causing disease
What is a missense mutation
Changes one AA for another
May alter bicohem properties of translated protein -> functional effect
May have no effect
What is a nonsense mutation
Insertion of premature stop codon -> prematurely truncated protein
High chance -> disease
What is a frameshift mutation
Shifts reading frame - stop codon is moved before or after where originally meant to be
Shortened or elongated protein
High likelihood of disease
What is splicing
RNA sequences transcribed from introns are excised -> only RNA transcribed from exons and spliced together then -> aa sequences
What are splice site muattions
Change in nucelic acids at introns = -1 and +2 just before or after exons - change splicing
Types of single nucloetide variants that are more likely to be pathogenic
Nonesense
Framshift
Splice site
What can insertions or deletions of more than one nucelic acid result in
Framshift mutation if cahnges aa code for
What is a triplet repeat
Repeat of amino acid motif at particular locus
What does unstable on transmission mean about a mutation
Gets bigger when pass down to chrildren
Progress from premutation to full mutation
Anticipation - more severe disease younger in childrne
What is anticipation
more severe disease younger in childrne with each generation
Examples of tiple repeat mutations
Myotonic dystrophy type 1 - DM1, CTG repeat in non coding DMPK
Huntingtions - CAG repeat
Number of repeats corresponds w phenotype
What can the problem be with genetic variants
Can be unsure if cause disease
- too common to cause or too rare to prove
Significance of genetic diagnosis
Reassurance of having diagnosis
Alter clinical management - treating, screening
Enrol in clinical trial, disease registires
Implications for wider family
Reproductive options
What areas use for classifying genetic variants
Phenotype
Population data
In silico or compuatational data
Family studies
Reported in disease database
Functional data - experiments/research
What effects how helpful matching phenotype to gene is
How specific pattern of features ass w gene is
How many different genes cause same phenotype/gene heterogenicity
What is OMIM
online mendelian inheritance in man - single variant and phenotypes ass with different gene variations
What do population data bases show
How common a genetic variant is
Therefore whether likely pathogenic
All healthy people
eg gnomAD
May find autosomal recessive disease - carrier frequency
What does in silico/compuatiional data predict
If variant expected to affect an important part of protein function - if it is then more likely to be pathogenic
Also how big biochemical difference between amino acids are eg charge
Computer programmes used
Polyphen, SIFT
Used in combo w other evidence
Family hisotry gathering
Variatn present in other affected family members
Absent in unaffected family members
Inherited as would expect eg parents cariers of autosomal recessive
Not always necessary
