10 - Evaluating Genomic Variants

Question 1

Purpose of genetic testing

Answer 1

• Accurate molecular diagnosis
• Disease prognosis
• Cascade screening (family members)
• Screening
• Monitoring

Question 2

Pathogenic variant

Answer 2

Capable of causing disease

Question 3

Benign variant

Answer 3

Not harmful in effect

Question 4

Mutation

Answer 4

ONLY pathogenic/disease causing variants

Question 5

Polymorphism

Answer 5

Variant that is common in a normal population

Question 6

Targeted detection of diagnostic variant

Answer 6

• Focuses on a specific gene location, size or region, and/or type of variant
• Diseases associated

Question 7

Why are these restrictions of detection chosen

Answer 7

• Ease of interpretation
• Proven clinical utility
• Limited resources

Question 8

Are all variants in an individuals DNA disease causing

Answer 8

Nah

Question 9

Steps in determining variant pathogenicity

Answer 9

• Determine if variant is known or novel (via disease associated or normal variant databases, literature)
• Seen locally?
• Critically appraise the evidence

Question 10

Nonsense and frameshift mutation pathogenicity

Answer 10

Assumed disease causing, provided that a loss of function/dominant negative effect is supported

Question 11

Synonymous variants and mutations not near genes pathogenicity

Answer 11

Assumed to be non disease causing

Question 12

Missense mutation pathogenicity

Answer 12

may have no effect, loss of function or gain of function

Question 13

Mutation

Answer 13

Change in DNA sequence that is probably disease causing

Question 14

Variant

Answer 14

Change in DNA sequence

Question 15

Mod of inheritance

Answer 15

Dominant, recessive, X linked, autosomal

Question 16

Alleles/zygosity

Answer 16

Heterozygous, homozygous, compound heterozygous, hemizygous

Question 17

Genomic location

Answer 17

Coding, promoter/regulatory, splice site

Question 18

Molecular change

Answer 18

• Substitution (synonymous, missense, nonsense)
• Deletion/insertion

Question 19

Functional effect

Answer 19

Loss/gain of function

Question 20

Homozygous

Answer 20

Same mutation present on both alleles

Question 21

Heterozygous

Answer 21

Mutation present on one allele only

Question 22

Compound heterozygous

Answer 22

Two different mutations present, one on each allele

Question 23

Hemizygous

Answer 23

On sex chromosomes, A mutation on one allele, and the other allele is absent

Question 24

De novo variant

Answer 24

Mutation found in child but not parents and is usually dominant disease

Question 25

Variants in trans

Answer 25

variants located on different copies of a homologous chromosome

Question 26

Filtering

Answer 26

• 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

Question 27

Amino acids that are highly conserved across species

Answer 27

Variant in these regions would be of high concern

Question 28

Functional data

Answer 28

• 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

Question 29

Goal of functional data studies

Answer 29

To understand the relationship between genetic variants and phenotype

Question 30

Variant hot spots

Answer 30

Disease causing variants have nonrandom distribution, occurring in specific functional domains