Molecular Pathology Practice Questions

Q: A couple has two children affected with tuberous sclerosis. On detailed clinical and laboratory evaluation, including molecular studies, both parents are normal. Which one of the following explains the presence of two affected children in this family?

Germline mosaicism. **Explanation:** **Tuberous Sclerosis Complex (TSC)** is an autosomal dominant disorder. In this scenario, the presence of two affected children from phenotypically and genetically normal parents (as confirmed by molecular studies) is best explained by **Germline Mosaicism**. 1. **Why Germline Mosaicism is correct:** This occurs when a mutation happens in a germline precursor cell (oocyte or sperm) during the parent's development. Consequently, a population of gametes carries the mutation, while the parent’s somatic cells (blood, skin) do not. This allows the parent to remain asymptomatic and test negative on standard molecular tests while passing the mutation to multiple offspring. 2. **Why other options are incorrect:** * **Non-penetrance:** This implies a parent *has* the genotype but does not show the phenotype. However, the question states molecular studies were normal, meaning the parents do not carry the mutation in their somatic DNA. * **Uniparental Disomy (UPD):** This involves inheriting two copies of a chromosome from one parent. It is associated with conditions like Prader-Willi or Angelman syndrome, not the recurrence of an autosomal dominant trait like TSC. * **Genomic Imprinting:** This refers to the differential expression of a gene depending on which parent it was inherited from. It does not explain how two normal parents produce affected children. **Clinical Pearls for NEET-PG:** * **TSC Genetics:** Mutations in *TSC1* (Hamartin, Chromosome 9) or *TSC2* (Tuberin, Chromosome 16). * **Vogt’s Triad:** Adenoma sebaceum (facial angiofibromas), mental retardation, and seizures (seen in <30%). * **High-Yield Signs:** Ash-leaf spots (earliest sign), Shagreen patches, Periungual fibromas (Koenen tumors), and Cardiac Rhabdomyomas (often regress). * **Rule of Thumb:** Whenever a "de novo" autosomal dominant condition recurs in siblings of normal parents, suspect **Germline Mosaicism**.

Q: The most common chromosomal syndrome is

Trisomy 21. **Explanation:** **Trisomy 21 (Down Syndrome)** is the correct answer because it is the most common chromosomal disorder and the most frequent genetic cause of intellectual disability worldwide. It occurs in approximately 1 in 700 to 800 live births. The prevalence is highly associated with advanced maternal age, primarily due to meiotic non-disjunction (95% of cases). **Analysis of Incorrect Options:** * **Fragile-X Syndrome:** This is the most common **inherited** cause of intellectual disability. However, it is a single-gene disorder (CGG repeat expansion in the FMR1 gene) rather than a numerical or structural chromosomal syndrome like Trisomy 21. * **Trisomy 18 (Edwards Syndrome):** This is the second most common autosomal trisomy. It is characterized by severe clinical features (clenched fists, rocker-bottom feet) and has a very high mortality rate in the first year of life. * **Trisomy 13 (Patau Syndrome):** This is the third most common autosomal trisomy. It presents with midline defects (holoprosencephaly, cleft lip/palate) and polydactyly, but it is significantly rarer than Trisomy 21. **High-Yield Clinical Pearls for NEET-PG:** * **Most common cause of Trisomy 21:** Maternal Meiotic Non-disjunction (95%). * **Most common cardiac defect:** Atrioventricular Septal Defect (Endocardial Cushion Defect). * **Hematological association:** Increased risk of Acute Megakaryoblastic Leukemia (AMKL/M7) before age 5 and ALL after age 5. * **Screening:** Increased Nuchal Translucency (NT) on ultrasound and decreased PAPP-A in the first trimester.

Q: A patient's karyotype shows the following. What clinical abnormality is expected?

Rockerbottom feet. ***Rockerbottom feet*** - **Trisomy 18 (Edwards syndrome)** characteristically presents with **rockerbottom feet** (convex-shaped soles) as a key diagnostic feature. - Other typical findings include **clenched fists with overlapping fingers**, **micrognathia**, and **ventricular septal defects**. *Gynecomastia with long thin limbs* - This combination is characteristic of **Klinefelter syndrome (47,XXY)**, not Trisomy 18. - **Klinefelter syndrome** presents with **tall stature**, **gynecomastia**, and **hypogonadism** in males. *Short stature with polydactyly* - **Polydactyly** (extra digits) is a hallmark feature of **Trisomy 13 (Patau syndrome)**, not Trisomy 18. - **Trisomy 13** also presents with **holoprosencephaly**, **cleft lip/palate**, and **microphthalmia**. *Webbed neck with widely spaced nipples* - These features are characteristic of **Turner syndrome (45,X)**, affecting females exclusively. - **Turner syndrome** also presents with **short stature**, **lymphedema**, and **coarctation of aorta**.

Q: A specific karyotype is observed in a female patient. Which of the following syndromes is associated with this karyotype?

Cri du chat syndrome. ***Cri du chat syndrome*** - Associated with a **deletion of the short arm of chromosome 5 (5p-)**, which is clearly visible on **karyotype analysis** as 46,XX,del(5p). - Characterized by a distinctive **high-pitched cry** resembling a cat's meow, along with **intellectual disability** and **microcephaly**. *Bloom syndrome* - Caused by mutations in the **BLM gene** on chromosome 15, diagnosed through **molecular genetic testing**, not karyotype. - Features include **growth retardation**, **sun-sensitive skin rash**, and increased risk of **malignancies**. *Fragile X syndrome* - Results from **CGG repeat expansion** in the **FMR1 gene** on the X chromosome, requiring **molecular analysis** for diagnosis. - Karyotype may show a **fragile site** on Xq27.3, but this is not reliably detected in standard karyotyping. *Angelman syndrome* - Caused by **deletion or mutation of UBE3A gene** on chromosome 15q11-q13, diagnosed by **methylation studies** or molecular testing. - Karyotype is typically **normal** unless there's a large deletion, which occurs in only 10-15% of cases.

Q: What is the trinucleotide repeat seen in Fragile X syndrome?

CGG. **Explanation:** **Fragile X Syndrome** is the most common inherited cause of intellectual disability and is characterized by a trinucleotide repeat expansion in the **FMR1 gene** located on the X chromosome [1]. 1. **Correct Option (A) CGG:** The expansion occurs in the 5' untranslated region of the FMR1 gene. Normal individuals have 6–50 repeats. In Fragile X, this expands to a "full mutation" of **>200 CGG repeats**, leading to hypermethylation of the promoter, gene silencing, and a deficiency of the Fragile X Mental Retardation Protein (FMRP) [1]. 2. **Incorrect Option (B) CTG:** This repeat is associated with **Myotonic Dystrophy** (Type 1). 3. **Incorrect Option (C) CAG:** This is the most common repeat in polyglutamine diseases, most notably **Huntington’s Disease** and Spinocerebellar Ataxias [1]. 4. **Incorrect Option (D) GAA:** This repeat is seen in the frataxin gene in **Friedreich’s Ataxia**. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Intellectual disability, large everted ears, and **macro-orchidism** (post-pubertal). * **Cytogenetics:** When cells are cultured in folate-deficient medium, the X chromosome shows a "fragile site" (breakage) at the distal long arm (Xq27.3) [2]. * **Anticipation:** The disease shows "anticipation," where the severity increases or age of onset decreases in successive generations due to further expansion of the repeats during oogenesis. * **Premutation (55–200 repeats):** Associated with Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) and Premature Ovarian Failure [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 177-181. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 186-187.

Q: Klinefelter syndrome is diagnosed by?

Karyotyping. **Explanation:** **Klinefelter syndrome (47, XXY)** is a chromosomal aneuploidy characterized by the presence of one or more extra X chromosomes in a male phenotype. 1. **Why Karyotyping is the Correct Answer:** Karyotyping is the **gold standard** for diagnosing chromosomal abnormalities. It involves visualizing the complete set of chromosomes in a cell (usually from peripheral blood lymphocytes) during metaphase. In Klinefelter syndrome, karyotyping reveals the classic **47, XXY** pattern (or mosaics like 46, XY/47, XXY), confirming the numerical chromosomal aberration that defines the disorder. 2. **Why Other Options are Incorrect:** * **USG Abdomen:** While it may be used to look for undescended testes or assess pelvic structures, it cannot identify the genetic cause. * **Triple Test:** This is a prenatal screening tool (measuring AFP, hCG, and estriol) used to assess the risk of Down syndrome or neural tube defects; it is not diagnostic for Klinefelter syndrome. * **Echocardiography:** Used to detect structural heart defects (like Mitral Valve Prolapse, which can occur in Klinefelter), but it is a supportive investigation, not a diagnostic one. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Features:** Tall stature, gynecomastia, small firm testes (testicular dysgenesis), and infertility (azoospermia). * **Biochemical Profile:** Hypergonadotropic hypogonadism (↑ FSH, ↑ LH, ↓ Testosterone) due to Leydig cell dysfunction and seminiferous tubule hyalinization. * **Barr Body:** Positive (unlike normal males) due to the extra X chromosome. * **Risk:** Increased risk of male breast cancer and extragonadal germ cell tumors.

Question 1

A couple has two children affected with tuberous sclerosis. On detailed clinical and laboratory evaluation, including molecular studies, both parents are normal. Which one of the following explains the presence of two affected children in this family?

Accepted Answer

Germline mosaicism

Answer

Non-penetrance

Answer

Uniparental disomy

Answer

Genomic imprinting

Question 2

The most common chromosomal syndrome is

Accepted Answer

Trisomy 21

Answer

Fragile-X Syndrome

Answer

Trisomy 18

Answer

Trisomy 13

Question 3

Which of the following genetic aberrations is not a causative mechanism in cases of Prader-Willi syndrome?

Accepted Answer

Single nucleotide polymorphisms (SNPs)

Answer

Gene deletions

Answer

Defective genomic imprinting

Answer

Uniparental disomy

Question 4

A patient's karyotype shows the following. What clinical abnormality is expected?

Accepted Answer

Rockerbottom feet

Answer

Gynecomastia with long thin limbs

Answer

Short stature with polydactyly

Answer

Webbed neck with widely spaced nipples

Question 5

A specific karyotype is observed in a female patient. Which of the following syndromes is associated with this karyotype?

Accepted Answer

Cri du chat syndrome

Answer

Bloom syndrome

Answer

Fragile X syndrome

Answer

Angelman syndrome

Question 6

Karyotyping can be used to diagnose which of the following diseases?

Accepted Answer

Klinefelter’s syndrome

Answer

Multiple myeloma

Answer

Niemann-Pick disease

Answer

Pemphigus

Question 7

What is the trinucleotide repeat seen in Fragile X syndrome?

Accepted Answer

CGG

Answer

CTG

Answer

CAG

Answer

GAA

Question 8

Which of the following statements is true regarding ataxia telangiectasia?

Accepted Answer

Increase in Alpha-fetoprotein (AFP)

Answer

Increases the risk of squamous cell carcinoma

Answer

Inherited in an autosomal dominant pattern

Answer

None of the above

Question 9

Klinefelter syndrome is diagnosed by?

Accepted Answer

Karyotyping

Answer

USG abdomen

Answer

Triple test

Answer

Echocardiography

Question 10

22q11 deletion leading to Di George syndrome is associated with which of the following?

Accepted Answer

Hypocalcemia

Answer

Hypokalemia

Answer

Hyperkalemia

Answer

Hypercalcemia

Molecular Pathology — MCQs

Molecular Pathology — MCQs

On this page

Practice by Chapter

Want unlimited practice?