Genetics and Disease — MCQs
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A 22-year-old man presents with sudden loss of vision in his right eye. Physical examination reveals subluxation of the right crystalline lens. Auscultation of the chest reveals a midsystolic click. Echocardiography shows a floppy mitral valve and a dilated aortic arch. The patient's brother and cousin have similar symptoms. He has been prescribed a beta-blocker. A genetic defect involving which of the following substances is most likely present in this patient?
Which of the following conditions is NOT inherited in an autosomal recessive pattern?
In X-linked recessive (XLR) diseases, a modified inheritance pattern called 'pseudodominance' occurs when?
Wilson's disease is inherited in which pattern?
Gene mutations in Cystic Fibrosis occur at which location on the chromosome?
Genetics and Disease Indian Medical PG Practice Questions and MCQs
Question 1: A 22-year-old man presents with sudden loss of vision in his right eye. Physical examination reveals subluxation of the right crystalline lens. Auscultation of the chest reveals a midsystolic click. Echocardiography shows a floppy mitral valve and a dilated aortic arch. The patient's brother and cousin have similar symptoms. He has been prescribed a beta-blocker. A genetic defect involving which of the following substances is most likely present in this patient?
- A. Collagen
- B. Dystrophin
- C. Fibrillin-1 (Correct Answer)
- D. NF1 protein
Explanation: ### **Explanation** The clinical presentation of **ectopia lentis (lens subluxation)**, **mitral valve prolapse (midsystolic click)**, and **aortic root dilation** in a young patient with a positive family history is classic for **Marfan Syndrome** [1], [3]. **1. Why Fibrillin-1 is Correct:** Marfan Syndrome is an **autosomal dominant** connective tissue disorder caused by a mutation in the **FBN1 gene** on chromosome 15 [3]. This gene encodes **Fibrillin-1**, a glycoprotein that serves as a major structural component of extracellular microfibrils [1]. These microfibrils form a scaffold for **elastin** deposition [2]. Defective fibrillin leads to: * **Skeletal:** Arachnodactyly and pectus deformities. * **Ocular:** Upward and outward (superotemporal) subluxation of the lens [1]. * **Cardiovascular:** Cystic medial necrosis of the aorta, leading to aneurysms, dissection, and mitral valve prolapse [3]. Beta-blockers are prescribed to reduce the rate of aortic dilation. **2. Why Other Options are Incorrect:** * **Collagen:** Defects in collagen synthesis (e.g., COL5A1/COL5A2) are seen in **Ehlers-Danlos Syndrome**. While EDS features joint hypermobility and aortic issues, it does not typically present with ectopia lentis [1]. * **Dystrophin:** Mutations in the dystrophin gene lead to **Duchenne or Becker Muscular Dystrophy**, characterized by progressive muscle weakness and pseudohypertrophy. * **NF1 protein (Neurofibromin):** Mutations lead to **Neurofibromatosis Type 1**, characterized by café-au-lait spots, Lisch nodules, and neurofibromas. **3. High-Yield Clinical Pearls for NEET-PG:** * **Lens Subluxation:** Marfan = **Upward** (Superior); Homocystinuria = **Downward** (Inferior). * **Most common cause of death:** Aortic dissection/rupture [3]. * **Steinberg Sign & Walker-Murdoch Sign:** Clinical bedside tests for arachnodactyly. * **Genetics:** FBN1 mutation also leads to increased **TGF-β** signaling, contributing to tissue weakening.
Question 2: Which of the following conditions is NOT inherited in an autosomal recessive pattern?
- A. Sickle cell anemia
- B. Phenylketonuria
- C. Marfan's syndrome (Correct Answer)
- D. Wilson's disease
Explanation: **Explanation:** The correct answer is **Marfan’s syndrome** because it follows an **Autosomal Dominant (AD)** inheritance pattern. It is caused by a mutation in the **FBN1 gene** on chromosome 15, which encodes **Fibrillin-1**, a critical glycoprotein for the structural integrity of the extracellular matrix. Since it is dominant, a single mutated allele from one parent is sufficient to cause the disease. **Analysis of Options:** * **Sickle cell anemia (A):** This is a classic **Autosomal Recessive (AR)** disorder caused by a point mutation in the HBB gene (Glu6Val). Clinical manifestation occurs only in the homozygous state (HbSS). * **Phenylketonuria (B):** An **AR** metabolic disorder involving a deficiency of the enzyme phenylalanine hydroxylase. It requires two defective alleles for the phenotype to appear. * **Wilson’s disease (D):** An **AR** disorder of copper metabolism caused by mutations in the **ATP7B gene** on chromosome 13. **NEET-PG High-Yield Pearls:** 1. **Marfan’s Syndrome:** Look for "Tall stature, Ectopia lentis (upward dislocation), and Aortic root dilatation." It exhibits **pleiotropy** (one gene affecting multiple systems). 2. **Mnemonic for AR diseases:** "Many Metabolic" diseases are AR (e.g., Glycogen storage diseases, Galactosemia, Cystic Fibrosis, and most enzyme deficiencies). 3. **Mnemonic for AD diseases:** "Structural" proteins are often AD (e.g., Marfan’s, Achondroplasia, Hereditary Spherocytosis, Osteogenesis Imperfecta) [1]. 4. **Exceptions:** Most enzyme deficiencies are AR, but **Hunter Syndrome** and **G6PD deficiency** are X-linked Recessive.
Question 3: In X-linked recessive (XLR) diseases, a modified inheritance pattern called 'pseudodominance' occurs when?
- A. One parent is an affected homozygote and the other is an unaffected homozygote.
- B. One parent is an unaffected heterozygote and the other is an affected homozygote. (Correct Answer)
- C. One parent is normal and the other is an unaffected heterozygote.
- D. Both parents are unaffected.
Explanation: **Explanation:** **Pseudodominance** refers to a situation where a recessive trait appears to follow a dominant inheritance pattern, appearing in every generation. In X-linked recessive (XLR) disorders, this occurs when an **affected male (XᵃY)** mates with a **carrier female (XᴬXᵃ)**. 1. **Why Option B is Correct:** In this scenario, the offspring have a 50% chance of being affected (XᵃXᵃ females or XᵃY males). Because the disease appears in both the parent and the offspring generations, it mimics an Autosomal Dominant or X-linked Dominant pattern. This is "pseudo" (false) dominance because the underlying genotype remains recessive. This is commonly seen in consanguineous populations or for high-frequency recessive alleles (e.g., Color Blindness). 2. **Why Other Options are Incorrect:** * **Option A:** If an affected male (XᵃY) mates with a normal homozygote female (XᴬXᴬ), all daughters are carriers and all sons are normal. No offspring are affected, so it does not mimic dominance. * **Option C:** This is the standard XLR carrier state. Only 50% of sons are affected; the trait typically skips generations. * **Option D:** If both parents are unaffected (and not carriers), no offspring will be affected. **High-Yield NEET-PG Pearls:** * **Lyonization (Skewed):** Another cause of affected females in XLR traits is "Inactivated X-chromosome" theory, where the normal X is silenced, allowing the mutant X to express. * **Turner Syndrome (45, XO):** Females with Turner syndrome can manifest XLR diseases (like Hemophilia) because they only have one X chromosome, similar to males. * **Common XLR Examples:** Hemophilia A/B, Duchenne Muscular Dystrophy, G6PD deficiency, and Color Blindness.
Question 4: Wilson's disease is inherited in which pattern?
- A. Autosomal recessive (Correct Answer)
- B. Autosomal dominant
- C. X-linked recessive
- D. X-linked dominant
Explanation: **Explanation:** Wilson’s disease (Hepatolenticular degeneration) is an **Autosomal Recessive (AR)** disorder caused by mutations in the **ATP7B gene** located on **Chromosome 13**. This gene encodes a P-type ATPase responsible for transporting copper into the bile for excretion and incorporating it into ceruloplasmin. A defect in this protein leads to toxic copper accumulation in the liver, brain (basal ganglia), and cornea [1]. **Analysis of Options:** * **Autosomal Recessive (Correct):** Most inborn errors of metabolism, including Wilson’s disease, Hemochromatosis, and Cystic Fibrosis, follow an AR pattern. Both parents must be carriers for a child to be affected (25% risk). * **Autosomal Dominant:** These disorders usually involve structural proteins (e.g., Marfan syndrome) or receptors (e.g., Familial Hypercholesterolemia). * **X-linked Recessive:** These typically affect males (e.g., Hemophilia, G6PD deficiency). Menkes disease, another copper metabolism disorder, is X-linked, which is a common point of confusion with Wilson's. * **X-linked Dominant:** Rare patterns seen in conditions like Alport syndrome or Vitamin D-resistant rickets. **High-Yield Clinical Pearls for NEET-PG:** * **Kayser-Fleischer (KF) Rings:** Copper deposition in the **Descemet’s membrane** of the cornea (best seen on slit-lamp exam). * **Diagnosis:** Low serum ceruloplasmin (<20 mg/dL), increased 24-hour urinary copper excretion, and increased hepatic copper content (Gold Standard). * **Treatment:** Chelating agents like **D-Penicillamine** (first-line historically) or Trientine. Oral **Zinc** is used for maintenance as it interferes with intestinal copper absorption. * **Neurological sign:** "Giant Panda Face" appearance on MRI midbrain [1].
Question 5: Gene mutations in Cystic Fibrosis occur at which location on the chromosome?
- A. Short arm of chromosome 7
- B. Long arm of chromosome 5
- C. Long arm of chromosome 7 (Correct Answer)
- D. Short arm of chromosome 3
Explanation: ### Explanation **Correct Option: C (Long arm of chromosome 7)** Cystic Fibrosis (CF) is an **autosomal recessive** multisystem disorder caused by mutations in the **CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)** gene [1]. This gene is located on the **long arm (q arm)** of **chromosome 7**, specifically at position **7q31.2**. The CFTR protein functions as a chloride channel in epithelial membranes; a defect leads to thick, viscid secretions in the lungs, pancreas, and reproductive tract [1]. [2] **Analysis of Incorrect Options:** * **Option A (Short arm of chromosome 7):** While the chromosome number is correct, the mutation is located on the long arm (q), not the short arm (p). * **Option B (Long arm of chromosome 5):** Chromosome 5 is associated with conditions like **Familial Adenomatous Polyposis (FAP)** (5q21) and **Cri-du-chat syndrome** (5p deletion), but not CF. * **Option D (Short arm of chromosome 3):** Chromosome 3 mutations are classically associated with **Von Hippel-Lindau (VHL) disease** (3p25) and Renal Cell Carcinoma. **High-Yield Clinical Pearls for NEET-PG:** * **Most Common Mutation:** The deletion of phenylalanine at position 508 (**ΔF508**) is the most frequent mutation worldwide (Class II defect: protein misfolding). * **Diagnosis:** The gold standard is the **Sweat Chloride Test** (Pilocarpine iontophoresis); a value **>60 mEq/L** is diagnostic. * **Infertility:** 95% of males with CF have **Congenital Bilateral Absence of Vas Deferens (CBAVD)**. * **Newborn Screening:** Elevated **Immunoreactive Trypsinogen (IRT)** is the initial screening marker. * **Microbiology:** *Pseudomonas aeruginosa* is the most common pathogen causing chronic pulmonary infections in older CF patients.
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