dna pathogenic variants Flashcards
what is the variant allele frequency
used to infer whether a variant comes from somatic cells or inherited from parents when a matched normal sample is not provided. A variant is potentially a germline mutation if the VAF is approximately 50% or 100%
define exon
a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.
define intron
a segment of a DNA or RNA molecule which does not code for proteins and interrupts the sequence of genes.
they are removed via splicing
what is alternative splicing
a cellular process in which exons from the same gene are joined in different combinations,
leading to different, but related, mRNA transcripts. These mRNAs can be translated to produce different proteins with distinct structures and functions — all from a single gene
what is exon shuffling
A molecular mechanism for the formation of new genes, where two or more exons from different genes are recombined between introns, yielding rearranged genes with altered functions.
allows new proteins to be made
what are the 8 types of variants that can mess up the genetic code
duplications of genes or parts of gene
deletions (whole gene or some exons )
variants within the regulatory sequence
splice site variants ( introns. It spliced out)
introduce premature stop codon nonsense variant
replace one amino acid in protein with another - mis sense variant
expansion of trinucleotide repeats
what are the 2 types of deletions
out of frame deletion
in frame deletion
what is an out of frame deletion
when the reading frame is completely disrupted
so no protein can be made
what is an in frame deletion
when the reading frame is not disrupted
some protein can be made
but it may shorter but still functional
what is splice site variant
A genetic alteration in the DNA sequence that occurs at the boundary of an exon and an intron (splice site). This change can disrupt RNA splicing resulting in the loss of exons or the inclusion of introns and an altered protein-coding sequence
so intron is not accurately removed and may be translated into a protein
what is a non sense variant
changes codon to stop
so instead of producing another amino acid the cell prematurely stops building a protein
where does an out of frame deletion produce a stop codon
either at deletion site or further long
RNA detaches from the ribosome and is eliminated
what is nonsense mediated decay
a translation-coupled mechanism that eliminates mRNAs containing premature translation-termination codons
aims to reduce errors in gene expression
what is a mis-sense variant
when there is a single base substitution
resulting in a different amino acid being produced
may or may not be pathogenic
may be a polymorphism of no functional significance
what is a pathogenic variant
the variant causes disease
what is polymorphism
refers to the presence of two or more variant forms of a specific DNA sequence that can occur among different individuals or populations
what is a tri-nucleotide repeat
occurs when the number of triplets present in a mutated gene is greater than the number found in a normal gene [1–3].
the number of triplets in the disease gene continues to increase as the disease gene is inherited
examples of tri- nucleotide repeat diseases. (3)
Huntington’s disease
myotonic dystrophy
fragile X
what is allelic heterogeneity
when there are lots of different variants in one gene eg cystic fibrosis
what is locus heterogeneity
when mutations in different genes give the same clinical condition eg hypertrophic cardiomyopathy
what are dominant variants
they manifest the disease phenotype in the heterozygous state
if you have the condition then there is one variant allele and one Normal allele
what are recessive variants
they only manifest the disease in the homozygous state
there have to be variants in both alleles
the majority of pathogenic variants are recessive
what are 3 mechanisms of dominance
loss of function variants
gain of function variants
dominant negative variants
what are loss of function variants
when there is only one allele functioning
most are recessive
if a pathway is very sensitive to the amount of gene product so that if only half is produced it cannot function and this will cause a problem
what is haplo-insufficiency
dominant phenotype in diploid organisms that are heterozygous for a loss-of-function allele.
what are gain of function variants
A type of mutation in which the altered gene product possesses a new molecular function or a new pattern of gene expression
can cause increased gene dosage and increased protein activity
example of gain of function variant
a variant may occur at the recognition site for protein degradation leading to an accumulation of undegraded protein within the cell
what are dominant negative variants
where the protein from the variant allele interferes with the protein from the normal allele
what do genetic tests depends on
clinical context
what are 7 types of genetic test
diagnostic
predictive
carrier
pre natal
preimplantation genetic diagnosis
screening
susceptibility
when do you use diagnostic test
when the patient has signs and symptoms suggesting a particular diagnosis
it’s used to confirm a clinical diagnosis using a molecular genetic test
requires informed consent
what is predictive testing
can provide information about whether or not someone will develop or is likely to develop a specific condition, usually at a later stage
usually done to at risk family members if it runs in their family
when do you use carrier testing
for autosomal recessive and X linked disorder
what is carrier testing
genetic testing that is used to determine if a person is a carrier for specific autosomal recessive diseases. This kind of testing is used most often by couples who are considering becoming pregnant to determine the risks of their child inheriting one of these genetic disorders
what are pre natal tests
genetic test performed in pregnancy where there is an increased risk of a specific condition affecting the fetus
examples of pre natal tests (2)
chorionic villus sample
amniocentesis
who does genetic screening target
target population
Not high risk families
example of genetic screening
newborn screening for cystic fibrosis
what is susceptibility testing
finds out if there is an increased or decreased risk for a multi factorial condition
this issue is only just emerging
