dna pathogenic variants

Question 1

what is the variant allele frequency

Answer 1

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%

Question 2

define exon

Answer 2

a segment of a DNA or RNA molecule containing information coding for a protein or peptide sequence.

Question 3

define intron

Answer 3

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

Question 4

what is alternative splicing

Answer 4

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

Question 5

what is exon shuffling

Answer 5

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

Question 6

what are the 8 types of variants that can mess up the genetic code

Answer 6

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

Question 7

what are the 2 types of deletions

Answer 7

out of frame deletion

in frame deletion

Question 8

what is an out of frame deletion

Answer 8

when the reading frame is completely disrupted

so no protein can be made

Question 9

what is an in frame deletion

Answer 9

when the reading frame is not disrupted
some protein can be made
but it may shorter but still functional

Question 10

what is splice site variant

Answer 10

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

Question 11

what is a non sense variant

Answer 11

changes codon to stop
so instead of producing another amino acid the cell prematurely stops building a protein

Question 12

where does an out of frame deletion produce a stop codon

Answer 12

either at deletion site or further long
RNA detaches from the ribosome and is eliminated

Question 13

what is nonsense mediated decay

Answer 13

a translation-coupled mechanism that eliminates mRNAs containing premature translation-termination codons

aims to reduce errors in gene expression

Question 14

what is a mis-sense variant

Answer 14

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

Question 15

what is a pathogenic variant

Answer 15

the variant causes disease

Question 16

what is polymorphism

Answer 16

refers to the presence of two or more variant forms of a specific DNA sequence that can occur among different individuals or populations

Question 17

what is a tri-nucleotide repeat

Answer 17

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

Question 18

examples of tri- nucleotide repeat diseases. (3)

Answer 18

Huntington’s disease
myotonic dystrophy
fragile X

Question 19

what is allelic heterogeneity

Answer 19

when there are lots of different variants in one gene eg cystic fibrosis

Question 20

what is locus heterogeneity

Answer 20

when mutations in different genes give the same clinical condition eg hypertrophic cardiomyopathy

Question 21

what are dominant variants

Answer 21

they manifest the disease phenotype in the heterozygous state

if you have the condition then there is one variant allele and one Normal allele

Question 22

what are recessive variants

Answer 22

they only manifest the disease in the homozygous state

there have to be variants in both alleles

the majority of pathogenic variants are recessive

Question 23

what are 3 mechanisms of dominance

Answer 23

loss of function variants

gain of function variants

dominant negative variants

Question 24

what are loss of function variants

Answer 24

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

Question 25

what is haplo-insufficiency

Answer 25

dominant phenotype in diploid organisms that are heterozygous for a loss-of-function allele.

Question 26

what are gain of function variants

Answer 26

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

Question 27

example of gain of function variant

Answer 27

a variant may occur at the recognition site for protein degradation leading to an accumulation of undegraded protein within the cell

Question 28

what are dominant negative variants

Answer 28

where the protein from the variant allele interferes with the protein from the normal allele

Question 29

what do genetic tests depends on

Answer 29

clinical context

Question 30

what are 7 types of genetic test

Answer 30

diagnostic
predictive
carrier
pre natal
preimplantation genetic diagnosis
screening
susceptibility

Question 31

when do you use diagnostic test

Answer 31

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

Question 32

what is predictive testing

Answer 32

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

Question 33

when do you use carrier testing

Answer 33

for autosomal recessive and X linked disorder

Question 34

what is carrier testing

Answer 34

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

Question 35

what are pre natal tests

Answer 35

genetic test performed in pregnancy where there is an increased risk of a specific condition affecting the fetus

Question 36

examples of pre natal tests (2)

Answer 36

chorionic villus sample
amniocentesis

Question 37

who does genetic screening target

Answer 37

target population

Not high risk families

Question 38

example of genetic screening

Answer 38

newborn screening for cystic fibrosis

Question 39

what is susceptibility testing

Answer 39

finds out if there is an increased or decreased risk for a multi factorial condition

this issue is only just emerging