Molecular Pathology Practice Questions

Q: Which of the following syndromes are caused due to genomic imprinting? I. Rubinstein Taybi syndrome II. Prader-Willi syndrome III. Angelman syndrome IV. Edward syndrome Select the correct answer using the code given below :

II and III. ***II and III (Correct Answer)*** - **Prader-Willi syndrome** and **Angelman syndrome** are classic examples of disorders caused by **genomic imprinting** defects on chromosome 15 [1]. - **Prader-Willi syndrome** results from the loss of paternal 15q11-q13 expression, while **Angelman syndrome** results from the loss of maternal 15q11-q13 expression [1]. - Both conditions demonstrate parent-of-origin effects, where the same chromosomal region causes different phenotypes depending on whether the mutation is inherited from the mother or father [1]. *II and IV (Incorrect)* - While Prader-Willi syndrome is linked to genomic imprinting, **Edward syndrome** (Trisomy 18) is caused by a chromosomal abnormality (an extra copy of chromosome 18), not genomic imprinting. - Edward syndrome presents with distinct clinical features like **micrognathia** and **rocker-bottom feet**, different from imprinting disorders. *I and IV (Incorrect)* - **Rubinstein-Taybi syndrome** is caused by mutations in the **CREBBP** gene or deletion of 16p13.3, which are not related to genomic imprinting. - **Edward syndrome** is a chromosomal aneuploidy (Trisomy 18), not a disorder of genomic imprinting. *I and III (Incorrect)* - **Rubinstein-Taybi syndrome** is a genetic disorder caused by mutations in the CREBBP or EP300 genes, and it is not associated with genomic imprinting. - Only **Angelman syndrome** among these two options is caused by genomic imprinting. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 181-182.

Q: Identify the gene commonly involved in the condition shown in the image?

BRAF V600E. ***BRAF V600E*** - The image displays cells with **Langerhans cell morphology**, including folded nuclei and abundant pale cytoplasm, which are characteristic of **Langerhans cell histiocytosis (LCH)** [1]. - The **BRAF V600E mutation** is the most common genetic alteration found in LCH, present in about 50-60% of cases and activating the MAPK pathway [1]. *RAS* - **RAS mutations** are frequently seen in various cancers, including colorectal adenocarcinoma, pancreatic adenocarcinoma, and non-small cell lung cancer. - While RAS pathway activation can occur in LCH, a direct RAS mutation is not the most common genetic driver; rather, downstream effectors like BRAF V600E are more prominent [1]. *RET* - **RET mutations** are primarily associated with **medullary thyroid carcinoma** (in both sporadic and inherited forms like MEN 2A and MEN 2B) and can also be found in certain types of lung cancer. - They are not a characteristic genetic alteration for Langerhans cell histiocytosis. *P53* - The **TP53 gene** encodes the tumor suppressor protein p53, and mutations in this gene are among the most frequent genetic alterations across a wide spectrum of human cancers. - Although p53 plays a critical role in cell cycle regulation and apoptosis, it is not a primary or common driver mutation specifically associated with Langerhans cell histiocytosis [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus, pp. 629-630.

Q: Which PCR technique is best suited for identifying a syndrome with multiple causative agents?

Multiplex PCR. ***Multiplex PCR*** - **Multiplex PCR** allows for the simultaneous amplification of **multiple DNA targets** in a single reaction, making it ideal for identifying syndromes with numerous potential causative agents. - This method uses **multiple primer pairs** in one reaction tube, each designed to amplify a specific target sequence, thus efficiently detecting various pathogens or genetic markers. *RT-PCR* - **Reverse Transcription PCR (RT-PCR)** is used to detect **RNA targets** by first converting RNA into cDNA, which is then amplified. - While useful for RNA viruses or gene expression studies, it is not primarily designed for simultaneous detection of multiple diverse causative agents in the same way as multiplex PCR. *Nested PCR* - **Nested PCR** uses two sets of primers in sequential reactions to **increase sensitivity and specificity** by reducing non-specific binding. - This technique is generally employed to detect very low copies of a specific target or to overcome issues with non-specific amplification, rather than for identifying multiple different agents concurrently. *Conventional PCR* - **Conventional PCR** amplifies a **single specific DNA target** using one pair of primers per reaction. [1] - It requires separate reactions for each potential causative agent, making it inefficient and labor-intensive when testing for a syndrome with multiple etiologies. **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. 56-57.

Q: The diagrammatic representation of the karyotype of an individual indicates a specific genetic abnormality. What is the diagnosis?

Prader-Willi syndrome. ***Prader-Willi syndrome*** - The karyotype shows an abnormality on **chromosome 15**, which is consistent with Prader-Willi syndrome caused by **deletion of 15q11-q13** inherited from the **paternal** chromosome or **maternal uniparental disomy**. - While PWS deletions are typically **submicroscopic**, larger deletions can occasionally be visible on standard karyotyping, particularly when they represent **class I deletions** that are more extensive and involve additional chromosomal material beyond the typical PWS critical region. *Angelman syndrome* - Although Angelman syndrome also involves **chromosome 15q11-q13 deletion**, it results from **maternal** deletion or **paternal uniparental disomy**, and presents with distinctly different clinical features. - Clinical presentation includes **severe intellectual disability**, **ataxia**, **seizures**, **absent speech**, and **inappropriate laughter** (happy demeanor), which differs significantly from the PWS phenotype. *DiGeorge syndrome* - DiGeorge syndrome is caused by **deletion of chromosome 22q11.2**, not chromosome 15 as shown in the karyotype. - Clinical features include **cardiac defects** (conotruncal abnormalities), **thymic hypoplasia**, **parathyroid hypoplasia** (hypocalcemia), **cleft palate**, and characteristic facial features (CATCH-22 syndrome). *Cri du Chat syndrome* - This syndrome results from **deletion of chromosome 5p** (short arm of chromosome 5), not chromosome 15 as indicated in the karyotype. - Characteristic features include **high-pitched cry** resembling a cat's meow in infancy, **intellectual disability**, **microcephaly**, and **distinctive facial features**.

Q: HNPCC has defect in which

Mismatch repair gene. ***Mismatch repair gene*** - **HNPCC (hereditary non-polyposis colorectal cancer)**, also known as Lynch syndrome, is caused by inherited mutations in genes responsible for **DNA mismatch repair** [1]. - These genes, such as **MLH1, MSH2, MSH6, and PMS2**, normally correct errors that occur during DNA replication, preventing the accumulation of mutations. *Base pair excision* - **Base excision repair** is a distinct DNA repair pathway that primarily fixes small base lesions, such as damaged or modified bases. - This mechanism is not primarily implicated in the development of HNPCC. *Point mutation* - A **point mutation** refers to a single nucleotide change in a DNA sequence, which can be the *result* of a defective repair mechanism but is not the defect itself. - While mismatch repair defects lead to an increased rate of point mutations, the underlying *defect* in HNPCC is in the repair system, not in the mutation type. *Nucleotide excision* - **Nucleotide excision repair** is a major pathway for removing bulky, helix-distorting DNA lesions, such as those caused by UV radiation. - Defects in this pathway are associated with conditions like **xeroderma pigmentosum**, not HNPCC. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Gastrointestinal Tract, p. 817.

Q: Which of the following is associated with defect in mismatch repair

Hereditary HNPCC. ***Hereditary HNPCC*** - **Hereditary Nonpolyposis Colorectal Cancer (HNPCC)**, also known as Lynch syndrome, is caused by inherited mutations in **DNA mismatch repair (MMR) genes** [1]. - Defective MMR leads to an accumulation of **mutations** in microsatellite regions, increasing the risk of colorectal and other cancers [1]. *MUTYH Associated Polyposis* - This condition is associated with mutations in the **MUTYH gene**, which plays a role in **base excision repair**, not mismatch repair [1]. - It leads to an increased risk of colorectal polyps and cancer, but through a different DNA repair pathway. *Bloom Disorder* - Bloom syndrome is caused by mutations in the **BLM gene**, which encodes a DNA helicase involved in **DNA replication** and repair. - It results in genomic instability, increased cancer risk, and characteristic growth retardation and photosensitivity, distinct from mismatch repair defects. *SCID* - **Severe Combined Immunodeficiency (SCID)** refers to a group of genetic disorders that impair the development and function of **T and B lymphocytes**. - While some forms involve defects in DNA repair enzymes vital for V(D)J recombination (**e.g., RAG enzymes, Artemis**), SCID is primarily an immune disorder and not directly associated with the mismatch repair pathway in the context of cancer predisposition like HNPCC. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Gastrointestinal Tract, p. 817.

Q: Best method for the detection of mutations with low allele frequency is:

Droplet digital PCR. ***Droplet digital PCR*** - **Droplet digital PCR (ddPCR)** offers superior sensitivity for detecting **low allele frequency mutations** by partitioning the sample into thousands of individual reactions. - This compartmentalization allows for the direct quantification of target DNA molecules without relying on a standard curve, making it highly accurate for rare mutation detection. *FISH* - **Fluorescence in situ hybridization (FISH)** primarily detects **chromosomal abnormalities** like translocations, deletions, or amplifications, rather than single-nucleotide variants or small indels with low allele frequencies [2]. - It visualizes genetic changes at a **cytogenetic level** on an intracellular basis, not typically for quantifying rare DNA mutations in a heterogeneous sample. *Sanger sequencing* - **Sanger sequencing** is the gold standard for **sequencing individual DNA fragments** but has a detection limit of around 15-20% for allele frequency, making it unsuitable for very low allele frequency mutations [1]. - It struggles to reliably detect minor alleles when they are present in a small proportion of the total DNA pool. *Nested PCR* - **Nested PCR** increases the sensitivity and specificity of amplification by using two sets of primers in a sequential manner but does not inherently provide the **quantification capability** or the same level of **low allele frequency detection** as ddPCR processes. - While sensitive for detecting target sequences, it is not designed for precise quantification of rare mutations in a background of wild-type sequences. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 185. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 185-186.

Q: What is the interpretation of the given pedigree chart?

Autosomal dominant. ***Autosomal dominant*** - The trait appears in **every generation**, indicated by affected individuals in the first, second, and third generations [1]. - Both males and females are affected relatively equally, and affected individuals transmit the trait to approximately half of their offspring, consistent with **vertical transmission** [1]. - **Male-to-male transmission** is present, which definitively rules out X-linked inheritance patterns [1]. *Incomplete penetrance* - This pattern would typically show some individuals who carry the disease-causing genotype but **do not express the phenotype** (unaffected). - In this pedigree, all individuals who are expected to express the trait based on the clear dominant pattern are indeed affected. *Autosomal recessive* - This mode of inheritance would typically show **skipped generations**, meaning affected individuals would often have unaffected parents who are carriers [1]. - In this chart, every affected individual has at least one affected parent, ruling out an autosomal recessive pattern [1]. X-linked dominant - In X-linked dominant inheritance, **no male-to-male transmission** would be observed, as fathers pass their X chromosome only to daughters. - The presence of affected males transmitting the trait to male offspring rules out this inheritance pattern. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 148-151.

Question 1

Which of the following syndromes are caused due to genomic imprinting?
I. Rubinstein Taybi syndrome
II. Prader-Willi syndrome
III. Angelman syndrome
IV. Edward syndrome

Select the correct answer using the code given below :

Accepted Answer

II and III

Answer

II and IV

Answer

I and IV

Answer

I and III

Question 2

A 23-year-old female with a height of 4 feet has a karyotype as shown in the image below. Which among the following indicates the correct etiology?

Accepted Answer

Turner syndrome

Answer

Klinefelter's syndrome

Answer

Down syndrome

Answer

Edward's syndrome

Question 3

Identify the gene commonly involved in the condition shown in the image?

Accepted Answer

BRAF V600E

Answer

RAS

Answer

RET

Answer

P53

Question 4

Which PCR technique is best suited for identifying a syndrome with multiple causative agents?

Accepted Answer

Multiplex PCR

Answer

RT-PCR

Answer

Nested PCR

Answer

Conventional PCR

Question 5

The diagrammatic representation of the karyotype of an individual indicates a specific genetic abnormality. What is the diagnosis?

Accepted Answer

Prader-Willi syndrome

Answer

Angelman syndrome

Answer

Cri du Chat syndrome

Answer

DiGeorge syndrome

Question 6

HNPCC has defect in which

Accepted Answer

Mismatch repair gene

Answer

Base excision repair

Answer

Point mutation

Answer

Nucleotide excision repair

Question 7

Which of the following is associated with defect in mismatch repair

Accepted Answer

Hereditary HNPCC

Answer

MUTYH Associated Polyposis

Answer

Bloom Disorder

Answer

SCID

Question 8

Best method for the detection of mutations with low allele frequency is:

Accepted Answer

Droplet digital PCR

Answer

FISH

Answer

Sanger sequencing

Answer

Nested PCR

Question 9

What is the interpretation of the given pedigree chart?

Accepted Answer

Autosomal dominant

Answer

Incomplete penetrance

Answer

Autosomal recessive

Answer

X-linked dominant

Question 10

Fluorescence in situ hybridization (FISH) is required in which of the following interpretations of Her2/neu?

Accepted Answer

2+

Answer

All of the options

Answer

1+

Answer

3+

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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