Molecular Pathology Practice Questions

Q: A 45-year-old female is suspected of having a specific balanced translocation based on clinical presentation. Which of the following tests would be most appropriate for rapid confirmation and detailed analysis of the suspected chromosomal rearrangement?

Fluorescence In Situ Hybridization (FISH). ***Fluorescence In Situ Hybridization (FISH)*** - **FISH** is commonly used for detecting **specific chromosomal rearrangements**, such as balanced translocations, deletions, and duplications [1]. - It uses **fluorescently labeled probes** that bind to specific regions of chromosomes, allowing for rapid visualization and confirmation under a microscope [1]. *Polymerase Chain Reaction (PCR)* - **PCR** is primarily used for **amplifying specific DNA sequences** and detecting sequence variations, not for visualizing chromosomal structural changes. - While it can detect small deletions or insertions if primers are designed appropriately, it cannot visualize or analyze a **balanced translocation**. *Micro-array* - **Microarray analysis** (e.g., Array Comparative Genomic Hybridization, aCGH) is excellent for detecting **unbalanced chromosomal abnormalities** (gains or losses of genetic material) [1]. - However, it cannot detect **balanced translocations** because there is no net gain or loss of genetic material, only a rearrangement [1]. *Next-Generation Sequencing (NGS)* - **NGS** can detect various genetic alterations, including single nucleotide variants, small insertions/deletions, and **copy number variations**. - While advances are being made, routine NGS for comprehensive detection of complex **chromosomal rearrangements**, especially balanced ones, can be challenging and often requires specialized bioinformatics pipelines. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187.

Q: Which molecular test is preferred for detecting HER2/neu amplification in breast cancer?

FISH. ***FISH*** - **Fluorescence in situ hybridization (FISH)** is the gold standard for detecting HER2/neu amplification in breast cancer [1,2]. - It provides accurate analysis of **HER2 gene copy number** and is essential for determining eligibility for HER2-targeted therapies [1,2]. *PCR* - Polymerase chain reaction (PCR) detects **DNA sequences**, but it does not provide information on gene copy number or amplification status. - It is more suited for **qualitative or quantitative DNA analysis**, rather than for evaluating specific gene amplifications like HER2. *NGS* - Next-generation sequencing (NGS) is a high-throughput method that sequences DNA but may not reliably quantify HER2 copy number directly. - It offers comprehensive genomic profiling, making it less appropriate for focused HER2 amplification testing compared to **FISH**. *Micro-array* - Micro-array involves analyzing multiple genes simultaneously, but it lacks the specificity and sensitivity needed for **HER2 amplification detection**. - It is not typically used for clinical HER2 testing due to complexity and the need for more refined techniques like **FISH**. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Breast, p. 1066. [2] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. (Basic Pathology) introduces the student to key general principles of pathology, both as a medical science and as a clinical activity with a vital role in patient care. Part 2 (Disease Mechanisms) provides fundamental knowledge about the cellular and molecular processes involved in diseases, providing the rationale for their treatment. Part 3 (Systematic Pathology) deals in detail with specific diseases, with emphasis on the clinically important aspects., pp. 256-259.

Q: 25-year-old man presents for a routine physical examination. The patient is tall and on examination, he was found to have an early diastolic murmur. His family pedigree is given below (image attached). Which of the following is the mode of inheritance by which the disease is likely to be transmitted?

Autosomal Dominant. ***Autosomal Dominant*** - The pedigree shows that the disease appears in every generation, and affected individuals have at least one affected parent (e.g., I-1 passes it to II-1, II-5, II-8). This pattern is characteristic of **dominant inheritance**. - Both males and females are affected, and affected fathers can pass the trait to their sons (e.g., I-1 to II-1), ruling out X-linked inheritance and supporting an **autosomal dominant** mode. *Autosomal Recessive* - In autosomal recessive inheritance, affected individuals typically have **unaffected parents** (who are carriers), and the disease often skips generations. This is not observed in the provided pedigree. - While both males and females can be affected, the presence of affected individuals in every generation and vertical transmission makes recessive inheritance unlikely. *X-Linked Recessive* - X-linked recessive disorders typically show more affected males than females, and affected fathers **cannot pass the trait to their sons**. The pedigree clearly shows affected females and father-to-son transmission (I-1 to II-1 and potentially II-8 to III-6), ruling out this pattern. - Also, all daughters of an affected father would be carriers, and some an affected mother would have affected offspring. *X-Linked Dominant* - In X-linked dominant inheritance, all daughters of an affected father would be affected, and there is no male-to-male transmission. - The pedigree shows instances where affected fathers (like I-1) have unaffected daughters (e.g., II-2, II-4, II-6, II-7), and affected mothers (II-5, II-8) have unaffected children, which contradicts X-linked dominant inheritance.

Q: Which single gene disorder does not follow Mendelian inheritance?

Fragile X-syndrome. ***Fragile X-syndrome*** - While Fragile X-syndrome follows **X-linked dominant inheritance** (a Mendelian pattern), it exhibits **atypical features** that distinguish it from classic Mendelian disorders - The **trinucleotide repeat expansion** (CGG repeats in *FMR1* gene) leads to **anticipation** - increasing severity across generations - Shows **reduced penetrance** - premutation carriers may be asymptomatic, and the phenotype depends on repeat number, not just gene presence - Among the given options, this represents the **most modified form of Mendelian inheritance** *Huntington's disease* - Classic **autosomal dominant** disorder with CAG trinucleotide repeat expansion in the *HTT* gene - Follows typical Mendelian inheritance: affected parent has 50% chance of passing the mutation to each child - Though it shows anticipation, the inheritance pattern itself is straightforward Mendelian *Retinoblastoma (hereditary)* - Clear **autosomal dominant** inheritance pattern due to *RB1* gene mutation - Follows Mendelian principles with high penetrance (~90%) - The "two-hit hypothesis" explains tumor development but doesn't alter the Mendelian inheritance pattern *Sickle cell disease* - Textbook **autosomal recessive** disorder caused by a point mutation in the beta-globin gene (HbS) - Perfectly follows Mendelian laws: requires two copies of the mutant allele for disease manifestation - Heterozygotes (carriers) show sickle cell trait, demonstrating co-dominance at the molecular level

Q: Which one of the following is an autosomal recessive disorder?

Albinism. ***Albinism*** - **Albinism** is an **autosomal recessive disorder** characterized by a partial or complete lack of melanin pigment in the skin, hair, and eyes [1], [2]. - This condition is inherited when an individual receives **two copies of the defective gene**, one from each parent [1]. *Huntington's disease* - **Huntington's disease** is an **autosomal dominant disorder**, meaning only one copy of the mutated gene is sufficient to cause the disease. - It is characterized by progressive neurodegeneration, leading to uncontrolled movements, cognitive decline, and psychiatric problems. *Marfan's syndrome* - **Marfan's syndrome** is an **autosomal dominant disorder** affecting connective tissue, primarily impacting the skeletal, ocular, and cardiovascular systems. - It results from a mutation in the **FBN1 gene** which encodes for fibrillin-1, a component of elastic fibers. *Neurofibromatosis-1* - **Neurofibromatosis type 1 (NF1)** is an **autosomal dominant disorder** caused by a mutation in the NF1 gene, leading to the growth of tumors along nerves. - Clinical features include **café-au-lait spots**, neurofibromas, and Lisch nodules. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 150-151. [2] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. (Basic Pathology) introduces the student to key general principles of pathology, both as a medical science and as a clinical activity with a vital role in patient care. Part 2 (Disease Mechanisms) provides fundamental knowledge about the cellular and molecular processes involved in diseases, providing the rationale for their treatment. Part 3 (Systematic Pathology) deals in detail with specific diseases, with emphasis on the clinically important aspects., pp. 119-120.

Q: In Turner's syndrome, which of the following is NOT typically observed?

Mental retardation. ***Mental retardation*** - While there may be some **cognitive difficulties**, severe mental retardation is **not a typical feature** of Turner's syndrome. - Individuals with Turner's syndrome generally have **normal intelligence**, though they may experience challenges in areas like spatial perception. *Short stature* - This is a **classic and almost universal finding** in Turner's syndrome, often one of the first features to be noted [1]. - It results from the **haploinsufficiency of genes** on the X chromosome, particularly the SHOX gene [1]. *Widely spaced nipple* - Often referred to as **shield chest**, this is a characteristic physical finding due to the **broad chest** and increased inter-nipple distance. - This feature, along with other dysmorphic traits, contributes to the distinctive phenotype. *Webbed neck* - A **short, broad neck with redundant skin folds** (webbing) is a common manifestation of Turner's syndrome. - This **lymphatic abnormality** is often present from birth and is a key diagnostic clue.

Q: Li-Fraumeni syndrome occurs due to mutation in which gene?

TP53. ***Correct Answer: TP53*** - Li-Fraumeni syndrome is an autosomal dominant hereditary cancer syndrome linked to germline mutations in the **TP53 tumor suppressor gene**. - The TP53 gene encodes the **p53 protein**, a critical regulator of the cell cycle and apoptosis, often called the "guardian of the genome." *Incorrect: CDKN2A* - Mutations in the **CDKN2A gene** are primarily associated with familial melanoma and pancreatic cancer. - This gene encodes two tumor suppressor proteins, **p16INK4a** and **p14ARF**, which regulate the cell cycle. *Incorrect: PTEN* - The **PTEN gene** is associated with Cowden syndrome, which increases the risk of benign and malignant tumors in various tissues, including breast, thyroid, and endometrium. - PTEN is a tumor suppressor gene involved in cell growth, proliferation, and apoptosis. *Incorrect: MDM2* - The **MDM2 gene** is an oncogene that inactivates the p53 tumor suppressor protein. - While it interacts with p53, MDM2 mutations or overexpression are not the primary cause of Li-Fraumeni syndrome; rather, they contribute to cancer development by inhibiting p53 function.

Question 1

A 45-year-old female is suspected of having a specific balanced translocation based on clinical presentation. Which of the following tests would be most appropriate for rapid confirmation and detailed analysis of the suspected chromosomal rearrangement?

Accepted Answer

Fluorescence In Situ Hybridization (FISH)

Answer

Polymerase Chain Reaction (PCR)

Answer

Micro-array

Answer

Next-Generation Sequencing (NGS)

Question 2

Which molecular test is preferred for detecting HER2/neu amplification in breast cancer?

Accepted Answer

FISH

Answer

NGS

Answer

Micro-array

Answer

PCR

Question 3

What is the effect of defective mismatch repair genes in Lynch syndrome on DNA replication fidelity and cancer risk?

Accepted Answer

Decreased replication fidelity; increased cancer risk

Answer

Increased replication fidelity; decreased cancer risk

Answer

No effect on replication fidelity; unchanged cancer risk

Answer

Increased DNA repair efficiency; reduced cancer risk

Question 4

In the context of molecular diagnostics, which method is the best for detecting chromosomal translocations?

Accepted Answer

FISH

Answer

Array CGH

Answer

Karyotyping

Answer

Sanger Sequencing

Question 5

25-year-old man presents for a routine physical examination. The patient is tall and on examination, he was found to have an early diastolic murmur. His family pedigree is given below (image attached). Which of the following is the mode of inheritance by which the disease is likely to be transmitted?

Accepted Answer

Autosomal Dominant

Answer

Autosomal Recessive

Answer

X-Linked Recessive

Answer

X-Linked Dominant

Question 6

Which single gene disorder does not follow Mendelian inheritance?

Accepted Answer

Fragile X-syndrome

Answer

Retinoblastoma (hereditary)

Answer

Huntington's disease

Answer

Sickle cell disease

Question 7

Which one of the following is an autosomal recessive disorder?

Accepted Answer

Albinism

Answer

Marfan’s syndrome

Answer

Neurofibromatosis-1

Answer

Huntington's disease

Question 8

In Turner's syndrome, which of the following is NOT typically observed?

Accepted Answer

Mental retardation

Answer

Short stature

Answer

Widely spaced nipple

Answer

Webbed neck

Question 9

Which of the following statements about Von Hippel-Lindau (VHL) syndrome is true?

Accepted Answer

Regular screening for clear cell carcinoma of the kidneys is essential.

Answer

It is an autosomal recessive condition.

Answer

Central nervous system involvement is rare.

Answer

The VHL gene acts as a growth promoter.

Question 10

Li-Fraumeni syndrome occurs due to mutation in which gene?

Accepted Answer

TP53

Answer

CDKN2A

Answer

PTEN

Answer

MDM2

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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