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Genetic Mutation Question Bank: Case-Based MCQs with Explanations
1. Which DNA repair mechanism primarily corrects replication errors such as base mispairing?
A. Base excision repair
B. Homologous recombination
C. Mismatch repair
D. Nucleotide excision repair
E. Direct repair
Correct Answer: C) Mismatch repair
Detailed Explanation:
Mismatch repair (MMR) is the primary DNA repair mechanism that corrects errors introduced during DNA replication, particularly base-base mismatches and insertion-deletion loops. This system identifies and removes the mismatched base on the newly synthesized strand and fills in the correct nucleotide using the parental strand as a template. MMR significantly enhances the fidelity of DNA replication.
Incorrect Options:
A) Base excision repair
This mechanism fixes small, non-helix-distorting base lesions like deaminated or oxidized bases. It is not specific for replication-associated errors like base mismatches.
B) Homologous recombination
This process repairs double-strand breaks using a sister chromatid as a template. It ensures error-free repair but is not involved in correcting replication errors like base mismatches.
D) Nucleotide excision repair
This pathway removes bulky DNA lesions, such as thymine dimers caused by UV radiation, and is not specialized for base mispairing from replication.
E) Direct repair
This mechanism directly reverses certain DNA damage without replacing the nucleotide, such as the repair of methylated guanine. It does not correct replication-induced mismatches.
2. Which of the following best defines a nonsense mutation?
A. A mutation that does not change the amino acid sequence
B. A mutation that adds or removes nucleotides
C. A mutation that substitutes one amino acid for another
D. A mutation that introduces a premature stop codon
E. A mutation that activates a silent gene.
Correct Answer: D) A mutation that introduces a premature stop codon
Detailed Explanation:
A nonsense mutation is a point mutation in a DNA sequence that converts a codon encoding an amino acid into a stop codon (e.g., UAG, UAA, or UGA). This leads to premature termination of translation, resulting in a truncated, usually nonfunctional protein. Nonsense mutations can cause severe consequences depending on the location of the mutation and the importance of the affected protein domain.
Incorrect Options:
A) A mutation that does not change the amino acid sequence
This describes a silent mutation, where the change in the DNA sequence does not alter the encoded amino acid due to the redundancy of the genetic code.
B) A mutation that adds or removes nucleotides
This refers to insertion or deletion mutations, which can lead to frameshift mutations if not in multiples of three, but not to nonsense mutations specifically.
C) A mutation that substitutes one amino acid for another
This is known as a missense mutation, which results in a codon that codes for a different amino acid, potentially altering protein function but not causing premature termination.
E) A mutation that activates a silent gene
This is not a standard definition for any specific mutation type. While epigenetic changes can lead to gene activation, they are not described as nonsense mutations.
3. A 4-year-old boy is diagnosed with retinoblastoma. Genetic testing reveals a mutation in the RB1 gene present in all his cells, including buccal swabs and blood samples. His family history includes multiple relatives with early-onset cancers.
Which of the following best describes the nature of this mutation?
A. Somatic mutation occurring in the retinal cells
B. Germline mutation with autosomal dominant inheritance
C. X-linked somatic mutation
D. Mitochondrial DNA mutation
E. De novo mutation with no risk to siblings
Correct Answer: B) Germline mutation with autosomal dominant inheritance
Detailed Explanation:
Retinoblastoma caused by a mutation in the RB1 gene present in all cells, including buccal swabs and blood samples, indicates a germline mutation. The inheritance pattern is autosomal dominant, meaning that only one mutated copy of the RB1 gene is sufficient to increase the risk of developing retinoblastoma and other cancers. The presence of a family history with multiple cases of early-onset cancer further supports this mode of inheritance.
Incorrect Options:
A) Somatic mutation occurring in the retinal cells
A somatic mutation would be limited to tumor tissue and not present in all cells of the body. Since the mutation is seen in multiple tissues (buccal, blood), it is not somatic.
C) X-linked somatic mutation
RB1 is located on chromosome 13, not on the X chromosome, and the mutation is germline, not somatic.
D) Mitochondrial DNA mutation
Mitochondrial DNA mutations are maternally inherited and affect genes involved in oxidative phosphorylation. They are not associated with RB1 or retinoblastoma.
E) De novo mutation with no risk to siblings
A de novo mutation may occur in one child without a family history. However, the strong family history of early-onset cancers indicates an inherited germline mutation rather than a de novo case.
4. A mutation causes the substitution of a hydrophobic amino acid for a polar one in the active site of an enzyme. The patient presents with symptoms of a metabolic disorder due to reduced enzyme activity.
What type of mutation is most likely responsible for this clinical presentation?
A. Silent mutation
B. Frameshift mutation
C. Missense mutation
D. Nonsense mutation
E. Chromosomal translocation
Correct Answer: C) Missense mutation
Detailed Explanation:
A missense mutation results in a single nucleotide change that leads to the substitution of one amino acid for another in the protein sequence. In this case, the mutation replaces a hydrophobic amino acid with a polar one in the active site of an enzyme, altering its structure and reducing its enzymatic activity—this is characteristic of a missense mutation. Such mutations can disrupt protein function, especially when they occur in critical regions like the active site.
Incorrect Options:
A) Silent mutation
A silent mutation does not alter the amino acid sequence due to the redundancy of the genetic code. It typically has no impact on protein function and would not cause a metabolic disorder.
B) Frameshift mutation
A frameshift mutation results from insertions or deletions that shift the reading frame, usually leading to extensive changes in the amino acid sequence and a premature stop codon. It does not typically result in a single amino acid substitution.
D) Nonsense mutation
This mutation introduces a premature stop codon, truncating the protein. While this could cause enzyme inactivity, it would not result in the substitution of one amino acid for another.
E) Chromosomal translocation
This involves a large-scale rearrangement of genetic material between chromosomes, which may lead to gene dysregulation or fusion but not a single amino acid substitution.
5. A researcher is studying the effects of UV radiation on human keratinocytes. After exposure, the DNA analysis reveals the damage.
Which type of mutation is most likely associated with this DNA damage?
A. Inversion mutation
B. Alkylation of cytosine
C. Formation of apurinic sites
D. Pyrimidine dimer
E. Base analog incorporation
Correct Answer: D) Pyrimidine dimer
Detailed Explanation:
Ultraviolet (UV) radiation causes covalent bonding between adjacent pyrimidine bases, especially thymine, in DNA. These pyrimidine dimers distort the DNA helix, disrupting normal base pairing and DNA replication. If unrepaired, they can lead to mutations and are strongly associated with skin cancers. This is the most characteristic DNA lesion caused by UV radiation, especially UVB.
Incorrect Options:
A) Inversion mutation
This refers to a segment of DNA being flipped within the chromosome. It’s typically caused by chromosomal breaks and rejoining, not UV radiation.
B) Alkylation of cytosine
Alkylating agents (not UV) introduce alkyl groups into bases like cytosine, leading to mispairing or strand breaks.
C) Formation of apurinic sites
These occur when purine bases (adenine or guanine) are lost from the DNA backbone, typically due to spontaneous hydrolysis or chemical damage—not UV light.
E) Base analog incorporation
Base analogs are chemically similar to DNA bases and can be incorporated during replication, causing mismatches. This type of damage is caused by chemical mutagens, not UV radiation.
6. A woman with a strong family history of breast and ovarian cancer undergoes genetic testing. The lab identifies a frameshift mutation in the BRCA1 gene.
Which of the following best explains the pathogenicity of this mutation?
A. It replaces one amino acid with another of similar charge
B. It causes misfolding due to a single base change
C. It introduces a stop codon, shortening the protein
D. It alters the reading frame, affecting all downstream codons
E. It does not alter the amino acid sequence
Correct Answer: D) It alters the reading frame, affecting all downstream codons
Detailed Explanation:
A frameshift mutation involves the insertion or deletion of nucleotides that are not in multiples of three, which shifts the reading frame of the genetic code. This misalignment alters every codon downstream of the mutation, typically resulting in an abnormal protein with a truncated or nonfunctional product. In the BRCA1 gene, such mutations can disrupt tumor suppressor function and significantly increase the risk of breast and ovarian cancers.
Incorrect Options:
A) It replaces one amino acid with another of similar charge
This describes a conservative missense mutation, which typically has minimal effects on protein function—not a frameshift.
B) It causes misfolding due to a single base change
This is more consistent with a missense mutation affecting protein folding, not a frameshift mutation.
C) It introduces a stop codon, shortening the protein
This defines a nonsense mutation; although a frameshift mutation may eventually lead to a premature stop codon, the core mechanism is the shift in the reading frame.
E) It does not alter the amino acid sequence
This describes a silent mutation, which does not change the protein sequence. Frameshift mutations, in contrast, have significant downstream effects.
7. A 16-year-old girl presents with symptoms of β-thalassemia. Genetic testing reveals a mutation of the β-globin gene, affecting RNA processing.
What is the most likely effect of this mutation?
A. Introduction of a premature stop codon in exon 1
B. Duplication of the entire β-globin gene
C. Disruption of mRNA splicing leading to abnormal protein
D. Activation of an upstream enhancer
E. Unchanged gene expression due to noncoding location
Correct Answer: C) Disruption of mRNA splicing leading to abnormal protein
Detailed Explanation:
Correct Answer: C) Disruption of mRNA splicing leading to abnormal protein
β-thalassemia is commonly caused by mutations that affect RNA processing, particularly mRNA splicing of the β-globin gene. These mutations can disrupt normal splice sites or create new cryptic ones, resulting in abnormal or nonfunctional β-globin proteins. This impaired hemoglobin synthesis leads to the clinical features of β-thalassemia, including anemia and ineffective erythropoiesis.
Incorrect Options:
A) Introduction of a premature stop codon in exon 1
While a nonsense mutation could lead to a truncated protein, the question specifies a mutation affecting RNA processing, not translation.
B) Duplication of the entire β-globin gene
Gene duplication would increase β-globin production, which is not associated with β-thalassemia (a condition caused by decreased or absent β-globin synthesis).
D) Activation of an upstream enhancer
Enhancer activation would typically increase transcription, which is not consistent with the decreased β-globin levels seen in β-thalassemia.
E) Unchanged gene expression due to noncoding location
If the mutation were in a noncoding region that does not affect splicing or regulation, it would not cause β-thalassemia. However, in this case, RNA processing is affected, implying the mutation lies within regulatory or splice site regions critical for proper expression.
8. Two siblings with different severities of symptoms have different mutations in the same gene. One has a missense mutation, while the other has a frameshift mutation.
Which of the following best explains the difference in severity?
A. Frameshift mutations often preserve protein function
B. Missense mutations always lead to complete protein loss
C. Frameshift mutations result in global downstream disruption
D. Missense mutations alter DNA methylation only
E. Both mutations are functionally identical
Correct Answer: C) Frameshift mutations result in global downstream disruption
Detailed Explanation:
Correct Answer: C) Frameshift mutations result in global downstream disruption
A frameshift mutation alters the reading frame of the gene, leading to completely different and often nonfunctional amino acid sequences downstream of the mutation. This usually results in the formation of a premature stop codon and a truncated, nonfunctional protein, often leading to more severe clinical manifestations. In contrast, a missense mutation changes only one amino acid, and its effect can range from mild to severe depending on the location and function of the affected residue.
Incorrect Options:
A) Frameshift mutations often preserve protein function
Incorrect—frameshift mutations typically disrupt protein function severely, not preserve it.
B) Missense mutations always lead to complete protein loss
This is false—missense mutations can have variable effects, and many are compatible with partial or full protein function.
D) Missense mutations alter DNA methylation only
Missense mutations affect the amino acid sequence, not epigenetic modifications like DNA methylation.
E) Both mutations are functionally identical
They are not—frameshift mutations generally lead to more profound disruption of protein structure and function compared to missense mutations.
9. A 3-year-old boy is brought to the pediatric clinic with signs of developmental delay, hypotonia, and episodes of vomiting. Genetic testing reveals a single nucleotide substitution in the gene encoding phenylalanine hydroxylase (PAH), leading to a change from arginine to tryptophan in the enzyme’s active site. Plasma phenylalanine levels are markedly elevated.
Which of the following best describes the nature of this mutation?
A) Silent mutation
B) Nonsense mutation
C) Frameshift mutation
D) Missense mutation
E) Splice site mutation
Correct Answer: D) Missense mutation
Detailed Explanation:
A missense mutation is a point mutation where one nucleotide is substituted, resulting in the replacement of one amino acid with another. In this case, the substitution of arginine with tryptophan in the active site of PAH disrupts enzyme function, leading to phenylketonuria (PKU), a classic example of a disease caused by a missense mutation.
Incorrect Options:
A) Silent mutation
This involves a nucleotide change that does not alter the amino acid sequence due to the redundancy of the genetic code. It would not affect protein function or cause disease in most cases.
B) Nonsense mutation
This mutation introduces a premature stop codon, leading to early termination of the protein. That’s not the case here, as the amino acid was altered, not truncated.
C) Frameshift mutation
Frameshift mutations result from insertions or deletions that disrupt the reading frame. A single-base substitution does not cause a frameshift.
E) Splice site mutation
This affects the regions where introns are removed from pre-mRNA, potentially altering mRNA splicing. This was not described in the case.
10. A 12-year-old girl presents with fatigue and pallor. Laboratory studies show microcytic hypochromic anemia. Genetic sequencing reveals a point mutation in the first exon of the β-globin gene, resulting in the creation of a premature stop codon. There is a strong family history of thalassemia.
What type of mutation is most likely responsible for her condition?
A) Missense mutation
B) Silent mutation
C) Nonsense mutation
D) Frameshift mutation
E) Splice site mutation
Correct Answer: C) Nonsense mutation
Detailed Explanation:
A nonsense mutation is a point mutation that results in a premature stop codon, leading to early termination of translation and truncated, nonfunctional proteins. In β-thalassemia, such mutations in the β-globin gene disrupt hemoglobin production and lead to anemia.
Incorrect Options:
A) Missense mutation
This would result in the substitution of one amino acid for another. While this could impact protein function, it does not produce a premature stop codon.
B) Silent mutation
This mutation changes the nucleotide but not the amino acid, so it typically has no clinical effect.
D) Frameshift mutation
This occurs due to insertions or deletions, not single nucleotide substitutions, and alters the reading frame, which is not indicated here.
E) Splice site mutation
This affects RNA splicing and is not the mechanism described. The mutation occurs in an exon, not a splice junction.
11. A 7-year-old boy is brought to the clinic with fatigue, frequent infections, and bruising. Blood smear reveals a high number of lymphoblasts. Cytogenetic analysis shows the formation of a BCR-ABL fusion gene.
Which of the following best describes the pathogenic mechanism involved in this condition?
A) Chromosome deletion resulting in tumor suppressor loss
B) Chromosomal duplication of oncogenes
C) Chromosomal translocation
D) Insertion of viral oncogenes into host genome
E) Frameshift mutation in a DNA repair gene
Correct Answer: C) Chromosomal translocation causes the formation of a fusion oncogene
Detailed Explanation:
The t(9;22)(q34;q11) translocation produces the Philadelphia chromosome, resulting in a BCR-ABL fusion gene. This fusion protein has constitutive tyrosine kinase activity, driving uncontrolled cell proliferation in chronic myeloid leukemia (CML) and sometimes acute lymphoblastic leukemia (ALL). This is a classic example of an oncogenic fusion gene formed by a balanced translocation.
Incorrect Options:
A) Chromosome deletion resulting in tumor suppressor loss
This describes deletions like those seen in retinoblastoma (RB1) or Li-Fraumeni syndrome (TP53), not translocations forming fusion proteins.
B) Chromosomal duplication of oncogenes
Gene amplification is a different mechanism seen in conditions like neuroblastoma (N-MYC) or HER2-positive breast cancer, not applicable here.
D) Insertion of viral oncogenes into host genome
This mechanism is relevant in viral cancers like HPV-related cervical cancer or EBV-related lymphomas—not in BCR-ABL driven leukemias.
E) Frameshift mutation in a DNA repair gene
This relates to disorders like Lynch syndrome or BRCA-related cancers, not to leukemias involving chromosomal translocation.
12. A 32-year-old woman presents with a painless neck mass. A biopsy confirms follicular lymphoma. Cytogenetic studies reveal a t(14;18)(q32;q21) translocation involving the BCL2 gene.
What is the most likely consequence of this chromosomal translocation?
A) Overexpression of anti-apoptotic protein
B) Impaired DNA repair due to gene deletion
C) Formation of an inactive fusion protein
D) Activation of a tumor suppressor gene
E) Chromosomal aneuploidy leading to genomic instability
Correct Answer: A) Overexpression of anti-apoptotic protein
Detailed Explanation:
The t(14;18) translocation places the BCL2 gene under the control of the immunoglobulin heavy chain (IgH) promoter, leading to increased expression of BCL2, an anti-apoptotic protein. This allows the survival of abnormal lymphocytes and contributes to lymphomagenesis in follicular lymphoma.
Incorrect Options:
B) Impaired DNA repair due to gene deletion
This applies to conditions like ataxia telangiectasia or BRCA mutations, not BCL2 translocation.
C) Formation of an inactive fusion protein
Unlike BCR-ABL, the t(14;18) translocation does not create a fusion protein but upregulates a normal gene.
D) Activation of a tumor suppressor gene
This translocation activates an oncogene (BCL2), not a tumor suppressor.
E) Chromosomal aneuploidy leading to genomic instability
Aneuploidy refers to abnormal chromosome numbers (like trisomy 21), not a balanced translocation like t(14;18).
13. A 2-year-old boy is brought in due to developmental delay, frequent infections, and characteristic facial features. Physical exam reveals a heart murmur. FISH analysis shows a microdeletion on chromosome 22q11.2.
Which of the following best explains the mechanism behind his clinical presentation?
A) Chromosomal translocation leading to gene fusion
B) Nonsense mutation in a growth factor gene
C) Gene deletion causing haploinsufficiency
D) Inactivation of a tumor suppressor by methylation
E) Expansion of trinucleotide repeats disrupting gene function
Correct Answer: C) Gene deletion causing haploinsufficiency
Detailed Explanation:
The child likely has DiGeorge syndrome (22q11.2 deletion syndrome), where a microdeletion causes the loss of one copy of several genes, including TBX1, leading to haploinsufficiency—a condition in which one copy of a gene is not sufficient to maintain normal function. This leads to cardiac defects, thymic hypoplasia (immunodeficiency), hypocalcemia, and facial abnormalities.
Incorrect Options:
A) Chromosomal translocation leading to gene fusion
This is typical in cancers (e.g., BCR-ABL in CML) and not relevant to DiGeorge syndrome.
B) Nonsense mutation in a growth factor gene
A nonsense mutation introduces a stop codon but is not the mechanism in this microdeletion syndrome.
D) Inactivation of a tumor suppressor by methylation
This refers to epigenetic silencing, seen in some cancers, not congenital microdeletions.
E) Expansion of trinucleotide repeats disrupting gene function
Seen in disorders like Fragile X syndrome and Huntington’s disease, not DiGeorge.
14. A newborn male presents with lethargy, poor feeding, and seizures. Her family history reveals a sibling who died in infancy. Genetic testing reveals a deletion of the UBE3A gene on the maternal chromosome 15q11–q13.
Which of the following syndromes is most likely in this child?
A) Prader-Willi syndrome due to paternal deletion
B) Rett syndrome due to MECP2 mutation
C) Angelman syndrome due to maternal gene deletion
D) Fragile X syndrome due to CGG expansion
E) Smith-Lemli-Opitz syndrome due to enzyme deficiency
Correct Answer: C) Angelman syndrome due to maternal gene deletion
Detailed Explanation:
Angelman syndrome is most commonly caused by deletion or mutation of the maternally inherited UBE3A gene on chromosome 15q11–q13. UBE3A is only expressed from the maternal allele in neurons due to genomic imprinting, so its deletion leads to severe neurodevelopmental issues, seizures, and a characteristic happy demeanor.
Incorrect Options:
A) Prader-Willi syndrome due to paternal deletion
This involves the paternal deletion of the same region (15q11–q13), but leads to hypotonia, obesity, and hypogonadism, not seizures and Angelman features.
B) Rett syndrome due to MECP2 mutation
This X-linked condition affects mostly girls, with regression and stereotypic hand movements, and is not due to a deletion on chromosome 15.
D) Fragile X syndrome due to CGG expansion
Caused by trinucleotide repeat expansion in the FMR1 gene, not by gene deletion.
E) Smith-Lemli-Opitz syndrome due to enzyme deficiency
Caused by a defect in cholesterol biosynthesis, not a chromosomal deletion.
15. A 10-year-old boy is evaluated for developmental delay, anxiety, and repetitive hand-flapping movements. His mother reports that he started talking later than his peers and has difficulty with social interactions. Genetic testing reveals transcriptional silencing of the FMR1 gene on the X chromosome.
Which of the following best describes the molecular mechanism causing this condition?
A) Missense mutation
B) Mitochondrial DNA deletion
C) Trinucleotide expansion
D) Frameshift mutation
E) Noncoding polymorphism
Correct Answer: C) Trinucleotide expansion
Detailed Explanation:
In Fragile X syndrome, the expansion of CGG repeats (>200 repeats) in the 5′ untranslated region (UTR) of the FMR1 gene leads to the hypermethylation and transcriptional silencing of the gene. The absence of FMRP (Fragile X Mental Retardation Protein) impairs synaptic development and function, resulting in intellectual disability and behavioral issues.
Incorrect Options:
A) Missense mutation
This describes a point mutation leading to an amino acid change; it doesn’t involve transcriptional silencing of the FMR1 gene.
B) Mitochondrial DNA deletion
Fragile X is X-linked, not mitochondrial. This choice refers to mitochondrial disorders like MELAS.
D) Frameshift mutation
Frameshift mutations involve insertions or deletions, it doesn’t involve transcriptional silencing of the FMR1 gene.
E) Noncoding polymorphism causes no clinical effects. However, Trinucleotide expansions in the FMR1 gene have clear pathological effects, especially when exceeding 200 repeats.
16. A 40-year-old man presents with mood changes, involuntary movements, and progressive cognitive decline. Family history reveals multiple affected relatives with similar symptoms appearing in midlife. Genetic testing confirms an expansion of CAG repeats in a gene located on chromosome 4.
Which of the following best describes the pathogenesis of this condition?
A) Nonsense mutation in a dopamine receptor gene
B) Trinucleotide expansion causing polyglutamine aggregation
C) Chromosomal deletion affecting the basal ganglia
D) Frameshift mutation impairing neurotransmitter release
E) Splice site mutation reducing mRNA stability
Correct Answer: B) Trinucleotide expansion causing polyglutamine aggregation
Detailed Explanation:
Huntington’s disease is caused by the expansion of CAG repeats (which encode glutamine) in the HTT gene on chromosome 4. The expanded polyglutamine tract leads to misfolded huntingtin protein, which forms toxic intracellular aggregates, particularly in neurons of the basal ganglia and cortex, resulting in motor, psychiatric, and cognitive symptoms.
Incorrect Options:
A) Nonsense mutation in a dopamine receptor gene
Huntington’s is not caused by a stop codon in a dopamine receptor—it’s due to a repeat expansion in the HTT gene.
C) Chromosomal deletion affecting the basal ganglia
There is no chromosomal deletion in Huntington’s; it is caused by repeat expansion, not the loss of genetic material.
D) Frameshift mutation impairing neurotransmitter release
Huntington’s disease does not involve frameshift mutations but CAG repeat expansion.
E) Splice site mutation reducing mRNA stability
Splice site mutations affect mRNA processing; they are not responsible for Huntington’s disease pathogenesis.
