L16: Mutation - Consequences at a gene, protein and chromosomal level

Question 1

What is the primary focus of clinical genetic testing in cases of suspected genetic disease?

Answer 1

To investigate if a genetic variant is pathogenic and determine its role in the disease

Question 2

What is ataxia-telangiectasia (A-T)?

Answer 2

A rare, autosomal recessive disorder that causes progressive neurodegeneration, immune deficiencies, and increased cancer risk

Question 3

What is the inheritance pattern of ataxia-telangiectasia?

Answer 3

Autosomal recessive, requiring both parents to pass on the mutated gene

Question 4

How do clinical geneticists differentiate between pathogenic and benign genetic variants?

Answer 4

By assessing factors like frequency, evolutionary conservation, and functional analysis through in silico and laboratory methods

Question 5

What does “compound heterozygous” mean?

Answer 5

Having two different mutations in the same gene, one from each parent, leading to a recessive disorder

Question 6

What is a “missense variant,” and why is it challenging to classify?

Answer 6

A genetic alteration that alters one amino acid, disrupting protein structure, function and interactions; challenging because it might or might not disrupt function

Question 7

What tools are used for in silico analysis of mutations?

Answer 7

• Computational tools and algorithms used to predict potential impacts of genetic variants without immediate lab testing
• Software like Mutation Taster, which predicts pathogenicity based on conservation, amino acid changes, and other factors

Question 8

What is a “variant of uncertain significance” (VUS)?

Answer 8

A genetic variant that lacks sufficient evidence to classify it as either pathogenic or benign

Question 9

How is a pathogenic mutation affecting protein function typically confirmed?

Answer 9

Through functional assays such as Western blots to analyse protein expression and activity

Question 10

What role does the ATM gene play in the context of A-T?

Answer 10

It encodes a protein critical for DNA repair; mutations can lead to loss of function, increasing cancer risk and neurodegeneration

Question 11

What is the significance of “genotype-phenotype correlation”?

Answer 11

Specific genetic mutations (genotype) influence the observable characteristics or disease severity (phenotype), with some mutations leading to more severe presentations than others

Question 12

How can X chromosome inactivation contribute to certain syndromes?

Answer 12

• In females, one X chromosome is randomly inactivated in each cell, leading to a mosaic effect that can impact phenotype
• This can also protect and reduce impacts of harmful mutations

Question 13

What can tortoiseshell cats teach us about X-chromosome inactivation?

Answer 13

Their coat colors are determined by X-linked genes, and random X inactivation leads to a mosaic of color patches

Question 14

What is chromosomal nondisjunction and its consequence?

Answer 14

Failure of chromosomes to separate during meiosis, leading to aneuploidies like trisomy 21 (Down syndrome)

Question 15

Describe the Philadelphia chromosome’s role in cancer

Answer 15

It’s a chromosomal abnormality where parts of chromosomes 9 and 22 exchange, causing a cancer fusing gene, resulting in chronic myeloid leukemia (CML)

Question 16

Why are modifier genes significant in genetic disorders?

Answer 16

They can influence the severity of a disease, even in individuals with the same primary mutation

Question 17

What is “nonsense-mediated mRNA decay”?

Answer 17

A process where unstable mRNA is degraded, often resulting from mutations that introduce premature stop codons

Question 18

What are the typical clinical features of ataxia-telangiectasia?

Answer 18

Progressive cerebellar ataxia, telangiectasia (dilated blood vessels), immune deficiencies, and increased sensitivity to radiation

Question 19

What is the role of kinase activity in the ATM protein?

Answer 19

ATM kinase is activated by DNA damage and initiates DNA repair, particularly after ionizing radiation

Question 20

Explain the term “loss of function” mutation

Answer 20

A mutation that results in reduced or no functional protein, often linked to severe disease phenotypes

Question 21

What is the importance of evolutionary conservation in assessing mutation impact?

Answer 21

Highly conserved amino acids across species indicate functional importance; mutations here are more likely to be pathogenic

Question 22

Describe “dominant negative” mutations

Answer 22

Mutations where a faulty allele interferes with the function of the normal allele, potentially worsening the phenotype

Question 23

What is a “Bayes classifier” in genetic testing?

Answer 23

A statistical tool that evaluates the probability of a variant being disease-causing based on various data points/multiple genetic indicators

Question 24

How do geneticists approach “variants of uncertain significance” (VUS)?

Answer 24

They analyze VUS with caution, often requiring additional functional or familial data to classify the variant definitively

Question 25

What are the different types of mutations that can impact gene function?

Answer 25

Deletions, nonsense mutations, frameshift mutations, missense mutations, and splice site changes

Question 26

What is “compound heterozygosity”?

Answer 26

A condition where two different mutations are present in the same gene, one on each allele, contributing to disease

Question 27

What does “chromosomal translocation” mean?

Answer 27

A rearrangement where parts of chromosomes break and reattach to different chromosomes, which can lead to genetic diseases

Question 28

Define “locus heterogeneity.”

Answer 28

• The occurrence of similar clinical features caused by mutations in different genes, however these genes lead to the same disease, important in diagnostics as multiple genes may need testing

Question 29

Why is whole-genome sequencing beneficial in clinical genetics?

Answer 29

Allows for comprehensive analysis of all genes, helping to identify potential causative genes when single-gene testing fails

Question 30

What is the genetic basis of Kleinfelter syndrome?

Answer 30

An extra X chromosome (47, XXY), often resulting in infertility, taller stature, and normal IQ

Question 31

What is aneuploidy?

Answer 31

A condition of having an abnormal number of chromosomes, such as trisomy (an extra chromosome) or monosomy (missing a chromosome)

Question 32

How do modifying genes affect disease phenotype?

Answer 32

• They can alter the severity or expression of a genetic disorder, even within the same family with identical primary mutations
• Difficult to identify as they often have subtle effects on phenotype, requiring large family studies and whole-genome sequencing to pinpoint their influence

Question 33

Why are modifying genes difficult to identify?

Answer 33

Often have subtle effects on phenotype, requiring large family studies and whole-genome sequencing to pinpoint their influence

Question 34

What is the impact of “non-disjunction” in meiosis?

Answer 34

It can lead to conditions like Down syndrome by failing to separate chromosomes properly, resulting in extra or missing chromosomes in offspring

Question 35

What are splice site mutations, and why are they significant?

Answer 35

Mutations that occur at the junctions of exons and introns, potentially disrupting mRNA splicing, leading to abnormal or truncated proteins

Question 36

What is a “Western blot,” and how is it used in genetic testing?

Answer 36

A technique for detecting specific proteins in a sample; it helps assess protein levels and activity to understand mutation effects

Question 37

What is “genetic heterogeneity”?

Answer 37

The phenomenon where different genetic mutations can cause similar phenotypes or diseases, complicating diagnosis and treatment

Question 38

How can phosphorylation studies be used in mutation analysis?

Answer 38

Phosphorylation changes can reveal if a mutation affects protein activation, particularly in proteins involved in cell signaling like ATM

Question 39

Describe “allelic heterogeneity.”

Answer 39

It occurs when different mutations in the same gene lead to the same or similar diseases, such as with different mutations in the ATM gene causing A-T

Question 40

Explain the concept of “frameshift mutations.”

Answer 40

Mutations that alter the reading frame of a gene, typically causing a protein to be truncated and lose function

Question 41

What is “mosaicism,” and how does it arise?

Answer 41

A condition where an individual has cells with different genetic compositions, often due to mutations occurring after fertilisation

Question 42

How does the loss of function in ATM affect patients with A-T?

Answer 42

The absence or inactivity of ATM kinase impairs DNA repair, leading to cellular sensitivity to DNA damage and increased cancer risk

Question 43

What is “nonsense mutation” and its usual outcome on proteins?

Answer 43

A mutation that introduces a premature stop codon, generally resulting in a truncated, nonfunctional protein

Question 44

What role do bioinformaticians play in whole-genome sequencing?

Answer 44

They analyze large data sets to identify candidate genes and variants that may be implicated in genetic disorders

Question 45

What is “gain of function” mutation, and how does it differ from loss of function?

Answer 45

A mutation that enhances or adds a new function to a protein, potentially leading to dominant or complex disease effects

Question 46

Describe “X-chromosome fragility” as seen in Fragile X syndrome

Answer 46

The X chromosome develops breaks or gaps, especially under certain conditions, which leads to intellectual disability

Question 47

What is “Locus heterogeneity,” and why is it relevant in genetic diagnostics?

Answer 47

It is when mutations in different genes lead to the same disease, important in diagnostics as multiple genes may need testing

Question 48

How do “Western blot” and “antibody staining” help in assessing protein activity?

Answer 48

Western blot detects specific proteins, while antibody staining reveals post-translational modifications like phosphorylation

Question 49

Why is ATM kinase activity tested with radiation exposure in A-T research?

Answer 49

Radiation activates ATM kinase in normal cells; lack of response indicates a defective ATM protein, helping confirm an A-T diagnosis