Genetic variants and classification

Question 1

Normal gene features

Answer 1

23 pairs of chromosmes
All separate from each other
All gees present
Nucleic acid sequence typical
2 copies of each autosomal chromosome

Question 2

What is aneuploidy

Answer 2

Too many or too few chromosomes eg monosomy = missing one, trisomy - one extra

Question 3

Common aneuplodies

Answer 3

Trisomy 21 (downs), 13, 18, sex - eg 45 X0 (Turners), 45XXX (kleinfelters)

Question 4

What is translocation balanced vs unbalaned

Answer 4

One chromosome stuck onto another = translocation
Balanced - no missing or extra -> normal
Unbalanced -> phenotypic effect

Question 5

What can detect a balanced translocation

Answer 5

Karyotype

Question 6

What is a copy number variant

Answer 6

Large chunks of DNA either duplicated or deleted

Question 7

How detect copy number variant

Answer 7

SNP array

Question 8

What type of genetic variation is di george syndrome

Answer 8

Copy number variant
22q11.2 deletion -> 78 genes only one copy

Question 9

What are introns

Answer 9

Non protein coding DNA between exons
Regulatory functions, splice sites

Question 10

What are exons

Answer 10

Code for proteins
Cause majority of genetic disease
Introns spliced out

Question 11

What is a synonymous subsitiution

Answer 11

Single nucleotide change - doesnt change waht aa coded for
No change in aa sequene
Low likelihood of causing disease

Question 12

What is a missense mutation

Answer 12

Changes one AA for another
May alter bicohem properties of translated protein -> functional effect
May have no effect

Question 13

What is a nonsense mutation

Answer 13

Insertion of premature stop codon -> prematurely truncated protein
High chance -> disease

Question 14

What is a frameshift mutation

Answer 14

Shifts reading frame - stop codon is moved before or after where originally meant to be
Shortened or elongated protein
High likelihood of disease

Question 15

What is splicing

Answer 15

RNA sequences transcribed from introns are excised -> only RNA transcribed from exons and spliced together then -> aa sequences

Question 16

What are splice site muattions

Answer 16

Change in nucelic acids at introns = -1 and +2 just before or after exons - change splicing

Question 17

Types of single nucloetide variants that are more likely to be pathogenic

Answer 17

Nonesense
Framshift
Splice site

Question 18

What can insertions or deletions of more than one nucelic acid result in

Answer 18

Framshift mutation if cahnges aa code for

Question 19

What is a triplet repeat

Answer 19

Repeat of amino acid motif at particular locus

Question 20

What does unstable on transmission mean about a mutation

Answer 20

Gets bigger when pass down to chrildren
Progress from premutation to full mutation
Anticipation - more severe disease younger in childrne

Question 21

What is anticipation

Answer 21

more severe disease younger in childrne with each generation

Question 22

Examples of tiple repeat mutations

Answer 22

Myotonic dystrophy type 1 - DM1, CTG repeat in non coding DMPK
Huntingtions - CAG repeat

Number of repeats corresponds w phenotype

Question 23

What can the problem be with genetic variants

Answer 23

Can be unsure if cause disease
- too common to cause or too rare to prove

Question 24

Significance of genetic diagnosis

Answer 24

Reassurance of having diagnosis
Alter clinical management - treating, screening
Enrol in clinical trial, disease registires
Implications for wider family
Reproductive options

Question 25

What areas use for classifying genetic variants

Answer 25

Phenotype
Population data
In silico or compuatational data
Family studies
Reported in disease database
Functional data - experiments/research

Question 26

What effects how helpful matching phenotype to gene is

Answer 26

How specific pattern of features ass w gene is
How many different genes cause same phenotype/gene heterogenicity

Question 27

What is OMIM

Answer 27

online mendelian inheritance in man - single variant and phenotypes ass with different gene variations

Question 28

What do population data bases show

Answer 28

How common a genetic variant is
Therefore whether likely pathogenic
All healthy people
eg gnomAD
May find autosomal recessive disease - carrier frequency

Question 29

What does in silico/compuatiional data predict

Answer 29

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

Question 30

Computer programmes used

Answer 30

Polyphen, SIFT
Used in combo w other evidence

Question 31

Family hisotry gathering

Answer 31

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