Molecular Pathology Practice Questions

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

Autosomal monosomy. ***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.

Q: Which of the following are examples of trinucleotide repeat mutations?

All of the options. ***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.

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

Acute Myeloid Leukemia (AML). ***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.

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

Gene TP53. ***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.

Q: Sex chromosome pattern in Klinefelter's syndrome is:

XXY. ***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.

Q: Which chromosome is involved in the pathogenesis of MEN1?

11. ***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.

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

Polysyndactyly. ***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.

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

Vulval cancer. ***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.

Question 1

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

Accepted Answer

Autosomal monosomy

Answer

Chromosomal monosomy

Answer

Autosomal trisomy

Answer

Chromosomal trisomy

Question 2

Which of the following is a chromosomal instability syndrome?

Accepted Answer

Bloom syndrome

Answer

Fanconi anemia

Answer

Ataxia-telangiectasia

Answer

None of the options

Question 3

Which of the following are examples of trinucleotide repeat mutations?

Accepted Answer

All of the options

Answer

Friedreich ataxia

Answer

Fragile X syndrome

Answer

Huntington's chorea

Question 4

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

Accepted Answer

Acute Myeloid Leukemia (AML)

Answer

Neurofibromatosis

Answer

Retinoblastoma

Answer

Breast cancer

Question 5

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

Accepted Answer

Gene TP53

Answer

Gene RB1

Answer

Gene BRCA1

Answer

Gene P21

Question 6

Which investigation is the gold standard for diagnosing Edwards syndrome?

Accepted Answer

Karyotype

Answer

MLPA

Answer

Microarray

Answer

FISH

Question 7

Sex chromosome pattern in Klinefelter's syndrome is:

Accepted Answer

XXY

Answer

XO

Answer

XX

Answer

XY

Question 8

Which chromosome is involved in the pathogenesis of MEN1?

Accepted Answer

11

Answer

10

Answer

12

Answer

13

Question 9

Which malformation is associated with mutations in the HOX gene?

Accepted Answer

Polysyndactyly

Answer

Holoprosencephaly

Answer

Mayer Rokitansky syndrome

Answer

Gorlin syndrome

Question 10

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

Accepted Answer

Vulval cancer

Answer

Breast cancer

Answer

Prostate cancer

Answer

Ovarian cancer

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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