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: Which one of the following correctly denotes the inheritance pattern of cystic fibrosis?

Autosomal Recessive. ***Autosomal Recessive*** - Cystic fibrosis is an **autosomal recessive** disorder, meaning an individual must inherit **two copies** of the defective gene (one from each parent) to develop the condition. - Parents who are **carriers** (having one normal and one defective gene) typically do not show symptoms but can pass the gene to their children. *X-linked Dominant* - In **X-linked dominant** inheritance, a single copy of a mutated gene on the X chromosome is sufficient to cause the disorder. - This pattern would show common inheritance in females and often more severe phenotypes in males, which is not characteristic of cystic fibrosis. *Autosomal Dominant* - **Autosomal dominant** disorders require only **one copy** of a mutated gene on a non-sex chromosome for the disease to manifest. - If cystic fibrosis were autosomal dominant, affected individuals would typically have an affected parent, and the disease would be much more prevalent than observed. *X-linked Recessive* - **X-linked recessive** disorders primarily affect males, as they have only one X chromosome. Females are typically carriers and less severely affected. - Cystic fibrosis affects males and females nearly equally, which rules out an X-linked recessive inheritance pattern.

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

Cystic fibrosis. ***Cystic fibrosis*** - **Cystic fibrosis** is caused by mutations in the **CFTR gene**, leading to defective chloride transport and thick, sticky mucus. - It is inherited in an **autosomal recessive pattern**, meaning an individual must inherit two copies of the mutated gene (one from each parent) to develop the disease. *Retinitis pigmentosa* - **Retinitis pigmentosa** is a group of inherited eye disorders, and while some forms are X-linked or autosomal dominant, a significant portion are also inherited in an **autosomal recessive pattern**. - However, it's not exclusively autosomal recessive, making cystic fibrosis a more definitive answer in this context. *Vitamin D resistant rickets* - **Vitamin D resistant rickets**, also known as **X-linked hypophosphatemic rickets**, is primarily inherited in an **X-linked dominant pattern**. - It is characterized by impaired renal phosphate reabsorption and skeletal abnormalities despite normal vitamin D levels. *Neurofibromatosis* - **Neurofibromatosis type 1 (NF1)** and **Neurofibromatosis type 2 (NF2)** are both inherited in an **autosomal dominant pattern**. - NF1 is characterized by **café-au-lait spots**, **neurofibromas**, and optical gliomas, while NF2 involves **bilateral vestibular schwannomas**.

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.

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

Which one of the following correctly denotes the inheritance pattern of cystic fibrosis?

Accepted Answer

Autosomal Recessive

Answer

X-linked Dominant

Answer

Autosomal Dominant

Answer

X-linked Recessive

Question 3

Which one of the following is an autosomal recessive disease?

Accepted Answer

Cystic fibrosis

Answer

Retinitis pigmentosa

Answer

Vitamin D resistant rickets

Answer

Neurofibromatosis

Question 4

Which one of the following is due to the monosomy of X-chromosome?

Accepted Answer

Turner's syndrome

Answer

Klinefelter's syndrome

Answer

Testicular feminization

Answer

Adrenogenital syndrome

Question 5

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 6

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 7

HNPCC has defect in which

Accepted Answer

Mismatch repair gene

Answer

Base excision repair

Answer

Point mutation

Answer

Nucleotide excision repair

Question 8

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 9

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 10

All of the following are tests done for Turner mosaic screening except?

Accepted Answer

Serum FSH

Answer

Karyotype

Answer

FISH

Answer

Buccal smear

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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