Molecular Pathology Practice Questions

Q: Which of the following statements is not true for FISH technique?

Interface FISH needs rapidly multiplying cells.. **Explanation:** Fluorescence In Situ Hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes to bind to specific DNA sequences on chromosomes. **1. Why Option B is the Correct Answer (The False Statement):** Unlike traditional karyotyping, which requires cells to be in the metaphase stage (requiring active cell culture and division), **Interphase FISH** can be performed on non-dividing cells. It does **not** require rapidly multiplying cells or cell culture. This allows for a much faster turnaround time because the clinician does not have to wait days for cells to grow in a lab. **2. Analysis of Other Options:** * **Option A (Rapid technique):** FISH is significantly faster than conventional cytogenetics. Results can often be obtained within 24–48 hours because the cell culture step is bypassed. * **Option C (Microdeletions):** FISH has high resolution. While standard karyotyping can only detect large structural changes (>5 Mb), FISH can identify submicroscopic **microdeletions** (e.g., 22q11.2 deletion in DiGeorge syndrome) by the absence of a fluorescent signal. * **Option D (Circulating tumor cells):** FISH is highly sensitive and can be used to detect and characterize rare **circulating tumor cells (CTCs)** in peripheral blood, aiding in cancer prognosis and monitoring. **Clinical Pearls for NEET-PG:** * **Gold Standard:** FISH is often the gold standard for detecting specific gene rearrangements (e.g., *BCR-ABL* in CML or *HER2/neu* amplification in breast cancer). * **Limitation:** You must know what you are looking for; FISH requires a specific probe for a suspected target. It cannot scan the entire genome blindly like a microarray. * **Key Applications:** Rapid prenatal diagnosis of trisomies (13, 18, 21) and identifying microdeletion syndromes (Prader-Willi, Williams, DiGeorge).

Q: Which type of cancer is NOT associated with BRCA2 mutation?

Liposarcoma. The **BRCA2 gene** (located on chromosome 13q) is a tumor suppressor gene involved in the repair of double-stranded DNA breaks via homologous recombination. While BRCA1 is primarily associated with breast and ovarian cancers, **BRCA2** has a broader spectrum of associated malignancies involving various epithelial tissues. **Why Liposarcoma is the correct answer:** Liposarcoma is a mesenchymal tumor (soft tissue sarcoma). There is no established clinical or genetic association between BRCA2 mutations and the development of liposarcoma. BRCA mutations typically predispose individuals to carcinomas (epithelial origin) rather than sarcomas. **Analysis of Incorrect Options:** * **Ovarian Cancer:** BRCA2 mutations significantly increase the lifetime risk of ovarian cancer (approximately 10-20%), typically presenting as high-grade serous carcinoma [1]. * **Prostate Cancer:** BRCA2 is the most important genetic risk factor for aggressive, high-grade prostate cancer in men, often occurring at an earlier age. * **Bile Duct Cancer (Cholangiocarcinoma):** BRCA2 mutations are associated with an increased risk of various gastrointestinal malignancies, including pancreatic, gallbladder, and bile duct cancers. **NEET-PG High-Yield Pearls:** * **BRCA1 vs. BRCA2:** BRCA1 has a higher risk for breast/ovarian cancer; BRCA2 has a higher risk for **male breast cancer**, pancreatic cancer, and prostate cancer [2]. * **Fanconi Anemia:** Biallelic mutation (homozygous) of BRCA2 (also known as FANCD1) leads to Fanconi Anemia Type D1. * **Associated Cancers (BRCA2):** Breast (male and female), Ovary, Pancreas, Prostate, Melanoma, and Bile duct. * **Treatment:** Cancers with BRCA mutations are particularly sensitive to **PARP inhibitors** (e.g., Olaparib) due to the concept of "synthetic lethality."

Q: Multifactorial inheritance is seen in which of the following conditions?

Cardiac septal defects. **Explanation:** **Multifactorial inheritance** refers to conditions caused by the complex interaction of multiple genes (polygenic) and environmental factors [2]. These diseases do not follow classic Mendelian patterns but often show a "threshold effect" and tend to cluster in families. **Why Cardiac Septal Defects are the Correct Answer:** Congenital heart diseases, including **Atrial Septal Defects (ASD)** and **Ventricular Septal Defects (VSD)**, are classic examples of multifactorial inheritance. While some cases are associated with chromosomal anomalies (like Down syndrome), the majority of isolated septal defects result from the cumulative effect of several low-penetrance genes combined with maternal environmental triggers (e.g., folate deficiency, viral infections, or teratogen exposure) [1]. **Analysis of Incorrect Options:** * **A. Neurofibroma (Neurofibromatosis Type 1):** This is an **Autosomal Dominant** condition caused by a mutation in the *NF1* gene on chromosome 17. * **B. Hemophilia:** This follows an **X-linked Recessive** inheritance pattern (Hemophilia A: Factor VIII deficiency; Hemophilia B: Factor IX deficiency). * **D. Hypophosphataemic Rickets:** This is the classic example of **X-linked Dominant** inheritance (Vitamin D-resistant rickets). **High-Yield Clinical Pearls for NEET-PG:** * **Common Multifactorial Conditions:** Cleft lip/palate, Neural tube defects, Pyloric stenosis, Hypertension, Type 2 Diabetes Mellitus, and Hirschsprung disease. * **Recurrence Risk:** In multifactorial inheritance, the risk of recurrence in first-degree relatives is approximately the square root of the population prevalence ($\sqrt{p}$). * **Threshold Model:** The disease manifests only when the combined genetic and environmental liability exceeds a specific threshold [2].

Q: In Down syndrome, the chromosomal abnormality is most commonly due to which of the following?

Maternal nondisjunction. **Explanation:** **1. Why Maternal Nondisjunction is Correct:** Down syndrome (Trisomy 21) is primarily caused by **meiotic nondisjunction**, where chromosomes fail to separate during gametogenesis. In approximately **95% of cases**, the extra chromosome 21 is derived from the mother. This occurs most frequently during **Meiosis I**. The risk of maternal nondisjunction increases significantly with **advanced maternal age** (typically >35 years) due to the prolonged "dictyotene" stage (prophase I) in which oocytes are arrested from fetal life until ovulation. **2. Analysis of Incorrect Options:** * **Translocation (Option A):** Accounts for only **3–4%** of cases (Robertsonian translocation, usually between chromosomes 14 and 21). Unlike nondisjunction, this is independent of maternal age and can be inherited from a carrier parent. * **Point Mutations (Option B):** Down syndrome is a **numerical chromosomal aberration** (aneuploidy), not a single-gene disorder or a change in the DNA sequence at a specific locus. * **Paternal Nondisjunction (Option C):** While nondisjunction can occur during spermatogenesis, it accounts for only about **5%** of Down syndrome cases. **3. High-Yield Clinical Pearls for NEET-PG:** * **Most common cause:** Maternal Meiosis I nondisjunction (95%). * **Mosaicism:** Accounts for ~1–2% of cases; caused by **mitotic** nondisjunction during early embryogenesis. * **Biochemical Screening (Quadruple Test):** Characterized by **decreased** AFP and Estriol, and **increased** hCG and Inhibin-A (Mnemonic: **HI** is **High** – **H**CG and **I**nhibin). * **First Trimester Screening:** Increased Nuchal Translucency (NT) and decreased PAPP-A. * **Associated Pathology:** Early-onset Alzheimer’s (APP gene on Ch 21), Endocardial cushion defects (ASD/VSD), and increased risk of ALL/AML (M7).

Question 1

A 39-year-old woman is evaluated for severe left hip pain after twisting her leg. She has bony deformities of the lower extremities with limited mobility. The patient had a history of precocious puberty and hyperthyroidism, which was managed by radioiodine therapy. Physical examination shows large, hyperpigmented macules with irregular borders located on the left shoulder, left side of the neck, and left buttock. Which of the following genes is involved in this condition?

Accepted Answer

GNAS

Answer

PTEN

Answer

RET

Answer

STK11

Question 2

Which of the following statements is not true for FISH technique?

Accepted Answer

Interface FISH needs rapidly multiplying cells.

Answer

It is a very rapid technique.

Answer

Even microdeletions can be identified.

Answer

Can detect circulating tumor cells.

Question 3

Which type of cancer is NOT associated with BRCA2 mutation?

Accepted Answer

Liposarcoma

Answer

Ovarian cancer

Answer

Prostate cancer

Answer

Bile duct cancer

Question 4

Multifactorial inheritance is seen in which of the following conditions?

Accepted Answer

Cardiac septal defects

Answer

Neurofibroma

Answer

Hemophilia

Answer

Hypophosphataemic rickets

Question 5

Which of the following is false regarding Fragile X syndrome?

Accepted Answer

Mutation in FMR1 gene

Answer

Second most common cause of mental retardation

Answer

Macroorchidism

Answer

High arched palate

Question 6

Ectrodactyly is an autosomal dominant trait that causes missing middle fingers (lobster claw malformation). A grandfather and grandson both have ectrodactyly, but the intervening father has normal hands by x-ray. Which of the following terms best applies to this family?

Accepted Answer

Incomplete penetrance

Answer

New mutation

Answer

Variable expressivity

Answer

Germinal mosaicism

Question 7

Which of the following is the primary cause of phenotypic heterogeneity?

Accepted Answer

Allele mutation

Answer

Variable penetrance

Answer

Allelic deletion

Answer

Variable expressivity

Question 8

Submicroscopic deletions of any size can be detected by which of the following methods?

Accepted Answer

Multiplex ligation-dependent probe amplification (MLPA)

Answer

Southern blotting

Answer

Cytogenomic array technology

Answer

Chromosome painting

Question 9

In Down syndrome, the chromosomal abnormality is most commonly due to which of the following?

Accepted Answer

Maternal nondisjunction

Answer

Translocation

Answer

Point mutations

Answer

Paternal nondisjunction

Question 10

Most common cause of Down's syndrome is:

Accepted Answer

Trisomy 21

Answer

Monosomy 21

Answer

Robertsonian translocation

Answer

Mosaicism

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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