Molecular Pathology Practice Questions

Q: Which gene mutation is seen in Marfan syndrome?

Fibrillin-1 gene. **Explanation:** **Marfan Syndrome** is an autosomal dominant connective tissue disorder characterized by mutations in the **FBN1 gene** located on **chromosome 15q21.1**. This gene encodes **Fibrillin-1**, a glycoprotein essential for the formation of elastic fibers in the extracellular matrix. Fibrillin-1 also plays a critical role in sequestering Transforming Growth Factor-beta (TGF-β); its deficiency leads to excess TGF-β signaling, resulting in the characteristic overgrowth of long bones and weakening of connective tissues. **Analysis of Incorrect Options:** * **FGFR-3 gene (Option B):** Mutations in the Fibroblast Growth Factor Receptor 3 gene lead to **Achondroplasia**, the most common cause of dwarfism. * **COL1A1 gene (Option C):** Mutations in Collagen Type 1 (COL1A1/COL1A2) are associated with **Osteogenesis Imperfecta**, characterized by bone fragility and blue sclera. * **Fibrillin-2 gene (Option D):** Mutations in the FBN2 gene (chromosome 5) cause **Beals Syndrome** (Congenital Contractural Arachnodactyly), which mimics Marfanoid features but presents with multiple joint contractures and "crumpled" ears. **High-Yield Clinical Pearls for NEET-PG:** * **Skeletal:** Arachnodactyly (long fingers), pectus excavatum/carinatum, and scoliosis. * **Ocular:** **Ectopia lentis** (dislocation of the lens), typically **superior-temporal** (upward). * **Cardiovascular:** The most serious complications are **Aortic Root Dilation** and Aortic Dissection. * **Diagnostic Criteria:** Based on the **Revised Ghent Nosology**, focusing on FBN1 mutation, aortic root aneurysm, and ectopia lentis.

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.

Question 1

What is a Leiden mutation?

Accepted Answer

Mis-sense mutation

Answer

Frame shift mutation

Answer

Tri nucleotide repeat mutation

Answer

Non-sense mutation

Question 2

Aneuploidy is seen with all except:

Accepted Answer

DiGeorge syndrome

Answer

Trisomy of chromosome 18 and 13

Answer

Trisomy 21

Answer

Klinefelter syndrome

Question 3

A 20-year-old woman has a Robertsonian translocation involving chromosome 21 and a second acrocentric chromosome. What is the theoretic likelihood of a functional trisomy 21 if one of her ova is fertilized by a normal sperm?

Accepted Answer

1 in 3

Answer

1 in 1

Answer

1 in 2

Answer

1 in 4

Question 4

Trisomy 13 is identified as:

Accepted Answer

Patau's syndrome

Answer

Edward's syndrome

Answer

Down's syndrome

Answer

Klinefelter's syndrome

Question 5

Which gene mutation is seen in Marfan syndrome?

Accepted Answer

Fibrillin-1 gene

Answer

FGFR-3 gene

Answer

COL1A1 gene

Answer

Fibrillin-2 gene

Question 6

Von Hippel-Lindau disease is associated with all of the following except?

Accepted Answer

Hemangioblastomas

Answer

Endolymphatic sac tumors

Answer

Pheochromocytoma

Answer

Islet cell tumors

Question 7

What is the function of the FMR1 protein?

Accepted Answer

It is coded by the FMR1 gene which has the (5′-CGG-3′) n repeat segments.

Answer

It is expressed in fragile X-associated mental retardation.

Answer

It is normally found in the brain and ovaries.

Answer

When defective, it is not sufficient to cause the fragile X-associated mental retardation syndrome.

Question 8

Which of the following statements regarding Down syndrome is FALSE?

Accepted Answer

It is the most common trisomy in humans.

Answer

It occurs due to meiotic non-disjunction of chromosome 21.

Answer

It is characterized by Trisomy 21.

Answer

The most common congenital heart defect (CHD) associated with it is an endocardial cushion defect.

Question 9

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 10

The most common chromosomal syndrome is

Accepted Answer

Trisomy 21

Answer

Fragile-X Syndrome

Answer

Trisomy 18

Answer

Trisomy 13

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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