Molecular Pathology Practice Questions

Q: Which of the following is not the karyotype of Turner syndrome?

46,X,i(Xp). ***46,X,i(Xp)*** - This karyotype indicates an **isochromosome of the short arm of the X chromosome**, with two copies of Xp and complete loss of Xq. - This results in **duplication of Xp material** (including the critical SHOX gene region), which **prevents the characteristic short stature** of Turner syndrome [1]. - While Xq material is lost, the **presence of two Xp arms protects against the Turner phenotype**, making this karyotype **NOT typically associated with Turner syndrome**. Just as the loss of SHOX is associated with short stature, excess copies are associated with tall stature [1]. - This is an extremely rare karyotype that does not produce the classic Turner syndrome features. *45,XO* - This is the **classic and most common karyotype for Turner syndrome** (about 50-60% of cases), characterized by complete absence of one X chromosome. - Results in characteristic features: **short stature, gonadal dysgenesis, webbed neck, cardiac anomalies**, and lymphedema. *46,X,r(X)* - This karyotype has a **ring X chromosome**, where both ends of the X chromosome have fused together, typically with loss of genetic material from both arms. - The loss of critical genes leads to **Turner syndrome phenotype** due to haploinsufficiency. - Ring X chromosomes account for approximately 5% of Turner syndrome cases. *46,X,i(X)(q10)* - This is an **isochromosome of the long arm of the X chromosome** (i(Xq)), with two copies of Xq and complete loss of Xp [1]. - The **loss of Xp material (including SHOX gene)** causes the characteristic **short stature and skeletal abnormalities** of Turner syndrome [1]. - This is the **second most common structural abnormality** causing Turner syndrome (15-20% of cases). **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 169-177.

Q: Which of the following statements is/are true:

All of the options. ***Correct: All of the options*** - All three statements accurately describe key concepts in genetic variation: mosaicism, chimerism, and clinical genetics of Turner syndrome. - Each statement is factually correct and represents important knowledge for medical examinations. *Correct Statement A: In a mosaic, genetically different cell types arise from a single zygote.* - **Mosaicism** occurs when a single fertilized egg develops into an individual with two or more genetically distinct cell lines - This results from **post-zygotic mutations** or chromosomal abnormalities during early embryonic cell divisions - Classic examples include McCune-Albright syndrome and some cases of chromosomal aneuploidies *Correct Statement C: Turner's syndrome survivors are often mosaics with a substantial fraction of normal cells.* - Many individuals with **Turner syndrome (45,X)** who survive have **mosaic karyotypes** such as 45,X/46,XX - The presence of a **normal 46,XX cell line** is associated with milder phenotypes and better survival - Mosaicism explains the wide phenotypic variability seen in Turner syndrome patients - However, non-mosaic 45,X individuals can also survive, though they may have more severe manifestations *Correct Statement D: In chimeras, they arise from more than one zygote.* - **Chimerism** occurs when cells from two or more different zygotes combine into a single individual - This can result from **fusion of dizygotic twin embryos** or maternal-fetal cell exchange - Unlike mosaics (one zygote → multiple cell lines), chimeras have cells from multiple fertilization events - Blood chimeras can occur after bone marrow transplantation

Q: Subtelomeric rearrangement of genes is frequently associated with intellectual disability. All of the following techniques can be used to diagnose them except:

MALDI. ***MALDI*** - **Matrix-assisted laser desorption/ionization (MALDI)** is a soft ionization technique used in mass spectrometry for analyzing biomolecules like proteins and peptides. - It is not suitable for detecting large-scale chromosomal rearrangements such as **subtelomeric deletions or duplications**. *FISH* - **Fluorescence in situ hybridization (FISH)** uses fluorescent DNA probes that bind to specific target regions on chromosomes, allowing for the detection of deletions or duplications [1]. - **Subtelomeric FISH** specifically targets the ends of chromosomes and is a common method for identifying subtelomeric rearrangements [1]. *MAPH* - **Multiplex amplifiable probe hybridization (MAPH)** is a technique used for detecting copy number variations (CNVs), including deletions and duplications, in specific genomic regions. - It can be applied to **subtelomeric regions** by designing probes specific to those areas, making it useful for diagnosing subtelomeric rearrangements. *CGH array* - **Comparative genomic hybridization array (CGH array)** is a high-resolution method that compares the patient's DNA to a control DNA to detect unbalanced chromosomal abnormalities across the entire genome [1]. - It is highly effective in identifying **copy number changes**, including subtelomeric deletions and duplications, associated with intellectual disability [1], [2]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, p. 187.

Q: What is the most common genetic abnormality in cystic fibrosis?

ΔF508. ***ΔF508*** - This mutation accounts for approximately **70% of all cystic fibrosis (CF) cases** worldwide, making it the most common genetic abnormality [1]. - It results in the deletion of a **phenylalanine residue** at position 508 in the **CFTR protein**, leading to misfolding and degradation [1]. *R117H mutation* - This is a rare **splice-site mutation** that can cause a milder form of CF or CFTR-related disorders. - It results in reduced CFTR protein function but is not the most common mutation. *G551D mutation* - This mutation is a **class III gating mutation**, meaning it impairs the opening of the **chloride channel** rather than its synthesis or trafficking. - It is relatively rare and is specifically targeted by CFTR modulator therapies like ivacaftor. *G542X mutation* - This is a **class I nonsense mutation** that introduces a premature stop codon, leading to a truncated and non-functional CFTR protein [1]. - While it causes severe CF, it is less common than the ΔF508 mutation. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Diseases of Infancy and Childhood, p. 476.

Q: A 34-year-old female with a family history of breast and ovarian cancer presents for genetic counseling. Which gene mutation increases her risk for both types of cancer?

BRCA1. **Correct: BRCA1** - **BRCA1** (and **BRCA2**) mutations are most strongly associated with an increased risk for both **hereditary breast cancer** and **ovarian cancer**, known as hereditary breast and ovarian cancer syndrome (HBOC) [1]. - These genes play a crucial role in **DNA repair** via homologous recombination, and their dysfunction leads to genomic instability and increased cancer susceptibility. - **BRCA1** mutation carriers have a **50-85% lifetime risk of breast cancer** and a **40-60% risk of ovarian cancer** [1]. *Incorrect: TP53* - The **TP53 gene** is a tumor suppressor gene linked to **Li-Fraumeni syndrome**, which increases the risk for various cancers, including breast cancer, sarcomas, brain tumors, and adrenocortical carcinoma. - While it increases breast cancer risk, ovarian cancer is not a prominent feature, and it is not the primary gene for **both breast and ovarian cancer** predisposition. *Incorrect: HER2* - **HER2** is an oncogene whose **amplification or overexpression** is associated with an aggressive subtype of breast cancer (HER2-positive breast cancer). - It is a **somatic alteration** (not germline), serving as a **prognostic and predictive biomarker** for targeted therapy (trastuzumab), not an inherited predisposition gene. *Incorrect: KRAS* - **KRAS** is an oncogene frequently mutated in **colorectal cancer**, pancreatic cancer, and lung cancer [2]. - It is involved in cell signaling pathways, but mutations in **KRAS are not associated with hereditary breast and ovarian cancer syndrome**. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Breast, pp. 1058-1059. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Pancreas, pp. 898-899.

Q: A family has a history of retinitis pigmentosa. The patient's pedigree chart shows multiple generations affected, with both males and females exhibiting the disease. What is the most likely pattern of inheritance?

Autosomal dominant. ***Autosomal dominant*** - The presence of the disease in **multiple generations** and affecting **both males and females** equally strongly suggests an autosomal dominant pattern. - In autosomal dominant inheritance, only **one copy of the altered gene** is needed to cause the disorder, leading to a high penetrance across generations. *Autosomal recessive* - This pattern typically shows affected individuals in a **single generation**, with unaffected carriers in previous generations, which is not consistent with "multiple generations affected." - For the disease to manifest, **two copies of the altered gene** (one from each parent) would be required, making it less likely to appear in consecutive generations without consanguinity. *X-linked recessive* - In X-linked recessive disorders, **males are predominantly affected**, and it often skips generations from an affected male to his grandsons through his carrier daughters. - While females can be affected, their presentation is typically milder or less common than in males, which contradicts "both males and females exhibiting the disease" over multiple generations. *Mitochondrial inheritance* - This pattern is characterized by inheritance **exclusively from the mother** to all her children, with no transmission from fathers. - Since the problem states both males and females are affected, and does not specify maternal-only transmission, this pattern is less likely.

Question 1

Which of the following is not the karyotype of Turner syndrome?

Accepted Answer

46,X,i(Xp)

Answer

45 XO

Answer

46,X,r(X)

Answer

46,X, i(X) (q10)

Question 2

Which of the following statements regarding banding is TRUE?

Accepted Answer

Trypsin and Giemsa are used

Answer

It is a method of detecting single gene deletion

Answer

Fluorescent filters are used

Answer

Y-chromosome is seen in interphase

Question 3

Which of the following statements is/are true:

Accepted Answer

All of the options

Answer

In a mosaic, genetically different cell types arise from a single zygote.

Answer

In chimeras, they arise from more than one zygote.

Answer

Turner's syndrome survivors are often mosaics with a substantial fraction of normal cells.

Question 4

Subtelomeric rearrangement of genes is frequently associated with intellectual disability. All of the following techniques can be used to diagnose them except:

Accepted Answer

MALDI

Answer

FISH

Answer

MAPH

Answer

cGH array

Question 5

Molecular genetic testing is used to detect all of the following except?

Accepted Answer

Translocation

Answer

Deletion

Answer

Amplification

Answer

Point mutation

Question 6

What is the most common genetic abnormality in cystic fibrosis?

Accepted Answer

ΔF508

Answer

R117H

Answer

G551D

Answer

G542X

Question 7

FISH can detect all except:

Accepted Answer

Point mutation

Answer

Deletion

Answer

Amplification

Answer

Translocation

Question 8

A 34-year-old female with a family history of breast and ovarian cancer presents for genetic counseling. Which gene mutation increases her risk for both types of cancer?

Accepted Answer

BRCA1

Answer

TP53

Answer

HER2

Answer

KRAS

Question 9

A family has a history of retinitis pigmentosa. The patient's pedigree chart shows multiple generations affected, with both males and females exhibiting the disease. What is the most likely pattern of inheritance?

Accepted Answer

Autosomal dominant

Answer

Autosomal recessive

Answer

X-linked recessive

Answer

Mitochondrial inheritance

Question 10

Which molecular technique is used to detect chromosomal translocations in cancers such as chronic myelogenous leukemia?

Accepted Answer

FISH

Answer

NGS

Answer

Sanger Sequencing

Answer

Southern Blot

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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