Molecular Pathology — MCQs

Molecular Pathology Indian Medical PG Practice Questions and MCQs

Question 231: Which genetic condition is considered the most lethal due to monosomy?

A. Autosomal monosomy (Correct Answer)
B. Chromosomal monosomy
C. Autosomal trisomy
D. Chromosomal trisomy

Explanation: ***Autosomal monosomy*** - **Autosomal monosomy** is the most lethal form of monosomy because it involves the loss of an entire autosome, leading to a severe imbalance in gene dosage. [1] - The human body cannot typically survive with the loss of a whole autosome, resulting in early embryonic or fetal demise. [1] *Chromosomal monosomy* - This is a broader term that includes both **autosomal monosomy** and **sex chromosome monosomy**. - While many forms of chromosomal monosomy are lethal, **sex chromosome monosomy (e.g., Turner syndrome)** is survivable, making the general term "chromosomal monosomy" less specific for the *most lethal* condition. [1] *Autosomal trisomy* - **Autosomal trisomy** involves an extra copy of an autosome (e.g., Trisomy 21 for Down syndrome), which, while causing significant health issues, is generally less lethal than the complete loss of an autosome. [1] - Many individuals with autosomal trisomies can survive to birth and beyond, unlike most cases of autosomal monosomy. [1] *Chromosomal trisomy* - This refers to having an extra copy of any chromosome, including **autosomes** and **sex chromosomes**. - While conditions like **Trisomy 13 (Patau syndrome)** and **Trisomy 18 (Edwards syndrome)** are highly lethal, the presence of *extra* genetic material is typically less universally lethal than the *absence* of an entire autosome. [1] **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 168-169.

Question 232: Which of the following is a chromosomal instability syndrome?

A. Bloom syndrome (Correct Answer)
B. Fanconi anemia
C. Ataxia-telangiectasia
D. None of the options

Explanation: ***Bloom syndrome*** - Bloom syndrome is the **classic chromosomal instability syndrome** characterized by **spontaneous chromosomal breaks, gaps, and markedly increased sister chromatid exchanges (SCEs)**. - It is an **autosomal recessive disorder** caused by mutations in the BLM gene (RecQ helicase family), leading to impaired DNA repair and replication [1]. - Patients exhibit **growth deficiency, photosensitive facial erythema, immunodeficiency**, and a dramatically **increased risk of cancers** at an early age. - The **hallmark laboratory finding** is a 10-fold increase in sister chromatid exchanges, making it the **prototypical chromosomal instability disorder**. *Fanconi anemia* - Fanconi anemia is **also a chromosomal instability syndrome**, characterized by **chromosomal breakage** when lymphocytes are exposed to DNA crosslinking agents (DEB/MMC test) [1]. - However, it presents primarily with **progressive bone marrow failure, congenital anomalies** (thumb/radial ray, café-au-lait spots, short stature), and increased cancer risk (particularly AML and squamous cell carcinomas). - While chromosomal instability is present, the **clinical presentation is dominated by bone marrow failure**, distinguishing it from Bloom syndrome. *Ataxia-telangiectasia* - Ataxia-telangiectasia is **also a chromosomal instability syndrome** with chromosomal breaks and translocations (especially involving chromosomes 7 and 14) [1]. - Caused by **ATM gene mutations**, leading to defective DNA double-strand break repair and cell cycle checkpoint control. - However, it is **clinically characterized primarily by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency**, and elevated AFP levels. - The **neurological manifestations predominate** the clinical picture, distinguishing it from Bloom syndrome. *None of the options* - This option is incorrect because Bloom syndrome is the **classic and prototypical chromosomal instability syndrome**, characterized predominantly by chromosomal instability features rather than other system involvement. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 322-323.

Question 233: Which of the following are examples of trinucleotide repeat mutations?

A. Friedreich ataxia
B. Fragile X syndrome
C. Huntington's chorea
D. All of the options (Correct Answer)

Explanation: ***All of the options*** - **Fragile X syndrome**, **Friedreich ataxia**, and **Huntington's chorea** are all well-known examples of genetic disorders caused by trinucleotide repeat expansions [1]. - The mutations involve an abnormal increase in the number of repetitions of a specific three-nucleotide sequence in the DNA [1]. *Fragile X syndrome* - This condition is caused by an expansion of the **CGG repeat** in the **FMR1 gene** on the X chromosome [1]. - The expansion leads to hypermethylation and silencing of the gene, impairing the production of fragile X mental retardation protein [1]. *Friedreich ataxia* - This is an autosomal recessive neurodegenerative disorder caused by an expansion of the **GAA repeat** in an intron of the **frataxin gene (FXN)**. - The repeat expansion interferes with transcription, leading to reduced frataxin protein levels. *Huntington's chorea* - This is an autosomal dominant neurodegenerative disorder caused by an expansion of the **CAG repeat** in the **huntingtin gene (HTT)**. - The expanded polyglutamine tract in the huntingtin protein leads to protein misfolding and neuronal damage, particularly in the striatum [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 177-181.

Question 234: Which of the following conditions is least associated with tumor suppressor genes?

A. Neurofibromatosis
B. Retinoblastoma
C. Acute Myeloid Leukemia (AML) (Correct Answer)
D. Breast cancer

Explanation: ***Multiple endocrine neoplasia*** - This syndrome involves mutations in **proto-oncogenes** like RET rather than tumor suppressor genes. - The condition is mainly characterized by the presence of **multiple endocrine tumors** rather than a failure of tumor suppression. *Retinoblastoma* - Associated with mutations in the **RB1 tumor suppressor gene**, leading to uncontrolled cell proliferation [1] [2]. - Classic example of **loss of function** in a tumor suppressor gene resulting in cancer, specifically in early childhood [1] [2]. *Neurofibromatosis* - Caused by mutations in **NF1** or **NF2 genes**, both of which function as tumor suppressors. - Leads to benign tumors such as **neurofibromas** and other neurogenic tumors due to malfunction in tumor suppression. *Breast cancers* - Often related to mutations in tumor suppressor genes such as **BRCA1** and **BRCA2**, which increase cancer risk [2]. - Implicated in the hereditary form of breast and ovarian cancers due to their roles in DNA repair and cell cycle regulation [2]. **References:** [1] 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. 227-228. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 298-302.

Question 235: Li–Fraumeni syndrome is associated with mutations in which of the following genes?

A. Gene RB1
B. Gene BRCA1
C. Gene P21
D. Gene TP53 (Correct Answer)

Explanation: ***Gene TP53*** - Li-Fraumeni syndrome is a rare, inherited cancer susceptibility syndrome associated with germline mutations in the **TP53 tumor suppressor gene**. - The **TP53 gene** encodes the p53 protein, which plays a critical role in cell cycle arrest, DNA repair, and initiation of apoptosis in response to cellular stress, thus preventing tumor formation. *Gene P21* - The **p21 gene** (CDKN1A) is a cyclin-dependent kinase inhibitor that acts downstream of p53, mediating p53-induced cell cycle arrest. - While p21 is involved in the p53 pathway, mutations in p21 itself are not the primary cause of Li-Fraumeni syndrome. *Gene RB1* - The **RB1 gene** encodes the retinoblastoma protein, a tumor suppressor involved in cell cycle regulation, particularly in controlling passage from G1 to S phase. - Mutations in **RB1** are primarily associated with hereditary retinoblastoma and osteosarcoma, not Li-Fraumeni syndrome. *Gene BRCA1* - The **BRCA1 gene** is a tumor suppressor gene involved in DNA repair, especially homologous recombination. - Germline mutations in **BRCA1** are strongly associated with hereditary breast and ovarian cancer syndrome, not Li-Fraumeni syndrome.

Question 236: Which investigation is the gold standard for diagnosing Edwards syndrome?

A. Karyotype (Correct Answer)
B. MLPA
C. Microarray
D. FISH

Explanation: ***Karyotype*** - A **karyotype** is considered the **gold standard** for diagnosing chromosomal abnormalities like **Edwards syndrome** (Trisomy 18) because it allows for the visualization and analysis of all 46 chromosomes [1]. - It can detect changes in chromosome number (aneuploidy) and large structural rearrangements, directly confirming the presence of an extra chromosome 18 [2]. *MLPA (Multiplex Ligation-dependent Probe Amplification)* - **MLPA** is a molecular technique used to detect **copy number variations** for specific targeted regions but does not provide a comprehensive view of the entire karyotype. - While it can detect trisomies, it is generally used for specific gene deletions or duplications and is not the first-line diagnostic method for whole chromosome aneuploidies like Edwards syndrome. *Microarray (Chromosomal Microarray Analysis)* - **Microarray** is a high-resolution method that can detect smaller deletions and duplications (microdeletions/microduplications) unidentifiable by traditional karyotyping. - However, for whole chromosome trisomies, a **karyotype** remains the gold standard as it directly visualizes the extra chromosome rather than inferring its presence through copy number changes of multiple probes [3]. *FISH (Fluorescence In Situ Hybridization)* - **FISH** is a targeted technique that uses fluorescent probes to detect specific chromosomal regions or whole chromosomes [3]. - While useful for rapid detection of common aneuploidies or specific translocations, it requires prior suspicion of a particular chromosomal abnormality and does not provide a comprehensive global view of all chromosomes like a traditional **karyotype** [3]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 167-168. [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. 54-55. [3] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187.

Question 237: Sex chromosome pattern in Klinefelter's syndrome is:

A. XXY (Correct Answer)
B. XO
C. XX
D. XY

Explanation: ***XXY*** - Klinefelter's syndrome is a **chromosomal disorder** that affects males, resulting from the presence of an extra X chromosome [2]. - The typical sex chromosome pattern is **XXY**, leading to a total of 47 chromosomes (47, XXY) [2]. - Clinical features include **tall stature**, **gynecomastia**, **small firm testes**, **infertility**, and **decreased testosterone** levels [2]. *XO* - This chromosomal pattern (45, XO) is characteristic of **Turner syndrome**, which affects females [1]. - Individuals with Turner syndrome typically present with **short stature**, **ovarian dysgenesis**, and a **webbed neck** [1]. *XX* - This is the normal sex chromosome pattern for a **female** (46, XX). - Females with this pattern typically develop normal **secondary sexual characteristics** and reproductive functions. *XY* - This is the normal sex chromosome pattern for a **male** (46, XY). - Males with this pattern typically develop normal **secondary sexual characteristics** and reproductive functions. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 173-174. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 174-175.

Question 238: Which chromosome is involved in the pathogenesis of MEN1?

A. 11 (Correct Answer)
B. 10
C. 12
D. 13

Explanation: ***11*** - **Multiple Endocrine Neoplasia type 1 (MEN1)** is caused by a germline mutation in the **MEN1 gene**, which is located on **chromosome 11** [1]. - The MEN1 gene acts as a **tumor suppressor gene**, and its inactivation leads to the development of tumors in the parathyroid glands, pituitary gland, and pancreatic islets [1]. *10* - Chromosome 10 is associated with other endocrine disorders, such as **Multiple Endocrine Neoplasia type 2 (MEN2)** due to mutations in the **RET gene** [1]. - However, it is **not involved** in the pathogenesis of MEN1. *12* - Chromosome 12 is generally **not directly implicated** in specific forms of Multiple Endocrine Neoplasia. - While it harbors many genes, none are definitively linked to MEN1. *13* - Chromosome 13 is notably associated with the **Retinoblastoma gene (RB1)**, a tumor suppressor gene involved in retinoblastoma and other cancers. - It plays **no direct role** in the genetic basis of MEN1. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Endocrine System, pp. 1104-1105.

Question 239: Which malformation is associated with mutations in the HOX gene?

A. Polysyndactyly (Correct Answer)
B. Holoprosencephaly
C. Mayer Rokitansky syndrome
D. Gorlin syndrome

Explanation: ***Polysyndactyly*** - The **HOX gene** plays a critical role in limb development and is associated with the malformation of **polysyndactyly**, which is characterized by extra fingers or toes [1]. - This condition is due to the disruption of the normal **patterning** during limb formation, directly involving the action of HOX genes [1]. *Gorlin syndrome* - Gorlin syndrome is primarily caused by mutations in the **PTCH1 gene**, linked to **basal cell carcinoma** and other abnormalities. - It does not involve HOX gene mutations, hence is **not** related to limb malformations. *Holoprosencephaly* - Holoprosencephaly is a developmental condition often linked to **chromosomal anomalies** and abnormal embryonic development, **not specifically** HOX gene mutations. - It refers to the incomplete separation of the forebrain, distinct from the **limb malformations** associated with HOX genes. *Mayer Rokitansky syndrome* - Mayer-Rokitansky syndrome involves **agenesis** or **hypoplasia** of the uterus and upper two-thirds of the vagina, which is due to other genetic factors. - This condition is not related to the functions of the **HOX genes** in limb or skeletal development. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Bones, Joints, and Soft Tissue Tumors, p. 1186.

Question 240: Which of the following cancers is least associated with BRCA2 mutations?

A. Breast cancer
B. Prostate cancer
C. Ovarian cancer
D. Vulval cancer (Correct Answer)

Explanation: ***Vulval cancer*** - While there may be some rare, sporadic cases, **vulval cancer** is generally not considered a primary cancer with a strong, well-established association with **BRCA2 mutations**. - Its etiology is more commonly linked to **HPV infection** and other risk factors not directly related to hereditary breast and ovarian cancer syndromes. *Breast cancer* - **BRCA2 mutations** are strongly associated with an increased lifetime risk of developing **breast cancer**, particularly for **male breast cancer**. - These mutations impair DNA repair mechanisms, leading to genomic instability that can result in cancerous transformation of breast tissue. *Prostate cancer* - Men with **BRCA2 mutations** have a significantly elevated risk of developing **prostate cancer**, often at an earlier age and with a more aggressive phenotype. - This association is well-documented, making BRCA2 testing relevant in high-risk prostate cancer populations. *Ovarian cancer* - **BRCA2 mutations** are a significant risk factor for **ovarian cancer**, particularly **high-grade serous ovarian cancer**. - The risk is substantial, though generally lower than that conferred by BRCA1 mutations for ovarian cancer in particular.

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