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?
What is the inheritance pattern of Marfan syndrome?
Which of the following is an X-linked recessive (XLR) condition?
Which of the following is NOT an acute porphyria?
Which of the following statements regarding the inheritance of Neurofibromatosis is FALSE?
Schizophrenia is a common presentation in which genetic disease?
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.
Question 6: What is the inheritance pattern of Marfan syndrome?
- A. Autosomal Dominant (Correct Answer)
- B. Autosomal Recessive
- C. X-linked Recessive
- D. X-linked Dominant
Explanation: **Explanation:** **Correct Answer: A. Autosomal Dominant** Marfan syndrome is an **autosomal dominant** connective tissue disorder caused by mutations in the **FBN1 gene** on chromosome **15q21** [1]. This gene encodes **fibrillin-1**, a glycoprotein essential for the structural integrity of the extracellular matrix and the regulation of Transforming Growth Factor-beta (TGF-̢) signaling. Because it is autosomal dominant, a single mutated allele is sufficient to cause the disease, and there is a 50% chance of transmission to offspring. It also exhibits **pleiotropy** (a single gene affecting multiple systems) and high **variable expressivity**. **Why other options are incorrect:** * **B. Autosomal Recessive:** These disorders typically involve enzyme deficiencies (e.g., Homocystinuria). Marfan syndrome involves structural protein defects, which usually follow dominant patterns [1]. * **C & D. X-linked:** Marfan syndrome affects males and females equally and shows male-to-male transmission, which rules out X-linked inheritance. **High-Yield Clinical Pearls for NEET-PG:** * **Cardiovascular:** The most common cause of death is **Aortic Root Dilatation** leading to aortic dissection or rupture. Mitral Valve Prolapse (MVP) is also common. * **Ocular:** **Ectopia Lentis** (dislocation of the lens) typically occurs **upwards and outwards** (Superior-temporal) [1]. *Contrast: Homocystinuria is downwards and inwards.* * **Skeletal:** Arachnodactyly (long fingers), positive **Wrist (Walker-Murdoch) sign**, and **Thumb (Steinberg) sign**. * **Steinberg Sign:** The thumb extends beyond the ulnar border of the hand when folded into the palm. * **Differential Diagnosis:** Always rule out **Homocystinuria**, which presents similarly but includes intellectual disability and increased risk of thrombosis.
Question 7: Which of the following is an X-linked recessive (XLR) condition?
- A. Cystic fibrosis
- B. Haemophilia (Correct Answer)
- C. Hereditary spherocytosis
- D. Neurofibromatosis
Explanation: **Explanation:** **Haemophilia (Option B)** is the correct answer. It is a classic example of an **X-linked recessive (XLR)** disorder [1]. In XLR conditions, the mutated gene is located on the X chromosome. Since males (XY) have only one X chromosome, a single mutated copy causes the disease. Females (XX) are typically asymptomatic carriers unless they have two mutated copies. Haemophilia A (Factor VIII deficiency) and Haemophilia B (Factor IX deficiency) both follow this inheritance pattern [1], leading to characteristic bleeding into joints (hemarthrosis) and muscles. **Why the other options are incorrect:** * **Cystic Fibrosis (Option A):** This is an **Autosomal Recessive (AR)** disorder caused by a mutation in the CFTR gene on chromosome 7. It requires two copies of the defective gene for phenotypic expression. * **Hereditary Spherocytosis (Option C):** This is primarily an **Autosomal Dominant (AD)** condition (in 75% of cases) involving defects in red blood cell membrane proteins like ankyrin or spectrin. * **Neurofibromatosis (Option D):** Both NF1 (chromosome 17) and NF2 (chromosome 22) are **Autosomal Dominant (AD)** disorders characterized by high penetrance and variable expressivity. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for XLR:** "**O**blivious **F**emale **G**ives **H**er **C**hild **D**isease" (**O**cular albinism, **F**abry disease, **G**6PD deficiency, **H**unter syndrome/Haemophilia, **C**hronic granulomatous disease, **D**uchenne muscular dystrophy). * **Rule of Thumb:** XLR disorders never show male-to-male transmission (fathers give their Y to sons). * **Lyonization:** In females, one X chromosome is randomly inactivated (Barr body), which can occasionally lead to "manifesting carriers" in XLR conditions.
Question 8: Which of the following is NOT an acute porphyria?
- A. Acute intermittent porphyria
- B. Variegate porphyria
- C. Hereditary coproporphyria
- D. Porphyria cutanea tarda (Correct Answer)
Explanation: Porphyrias are metabolic disorders caused by deficiencies in enzymes of the heme biosynthetic pathway. They are clinically classified into **Acute Porphyrias** (presenting with neurovisceral crises) and **Cutaneous Porphyrias** (presenting with skin photosensitivity) [1]. ### **Why Porphyria Cutanea Tarda (PCT) is the Correct Answer** PCT is the most common type of porphyria worldwide [1]. It is classified as a **chronic cutaneous porphyria**, not an acute one. It results from a deficiency of **Uroporphyrinogen decarboxylase (UROD)**. Clinically, it presents with skin fragility, blistering, and hyperpigmentation on sun-exposed areas (hands and face), often triggered by alcohol, iron overload, or Hepatitis C [1]. It does **not** cause the acute abdominal pain or neurological symptoms characteristic of acute porphyrias. ### **Analysis of Incorrect Options (Acute Porphyrias)** The following are classified as acute porphyrias because they involve the accumulation of neurotoxic precursors (ALA and PBG): * **Acute Intermittent Porphyria (AIP):** The most common acute porphyria. It presents with the "5 Ps": Painful abdomen, Polyneuropathy, Psychosis, Pink urine, and Precipitation by drugs [1]. * **Variegate Porphyria (VP) & Hereditary Coproporphyria (HCP):** These are "mixed" porphyrias. They are classified as acute because they cause neurovisceral crises, but they can also present with cutaneous photosensitivity. ### **NEET-PG High-Yield Pearls** * **Enzyme Deficiencies:** * AIP: Porphobilinogen deaminase (PBGD). * PCT: Uroporphyrinogen decarboxylase (UROD). * **Diagnosis:** The first-line screening test during an acute attack is checking for elevated **urinary Porphobilinogen (PBG)**. * **Management:** Acute attacks are treated with **IV Hemin** (suppresses ALA synthase) and high-dose glucose. * **Key Trigger:** Barbiturates and sulfonamides are notorious for precipitating acute attacks [1].
Question 9: Which of the following statements regarding the inheritance of Neurofibromatosis is FALSE?
- A. Von Recklinghausen's Disease is due to a defect in chromosome 17.
- B. It follows an autosomal dominant pattern of inheritance.
- C. NF-2 is characterized by musculoskeletal deformities. (Correct Answer)
- D. NF-1 is the most common single gene disorder affecting the human nervous system.
Explanation: **Explanation:** The correct answer is **C** because musculoskeletal deformities (such as sphenoid wing dysplasia, pseudoarthrosis of the tibia, and scoliosis) are hallmark features of **Neurofibromatosis Type 1 (NF-1)**, not NF-2. NF-2 is primarily a central neurogenic disorder characterized by bilateral vestibular schwannomas [1] and other intracranial/spinal tumors. **Analysis of Options:** * **Option A (True):** Von Recklinghausen's Disease (NF-1) is caused by a mutation in the *NF1* gene located on **chromosome 17** (17q11.2). This gene encodes **neurofibromin**, a tumor suppressor that regulates the Ras pathway. * **Option B (True):** Both NF-1 and NF-2 follow an **autosomal dominant** inheritance pattern. However, approximately 50% of cases arise from *de novo* mutations. * **Option D (True):** NF-1 is indeed the most common single-gene disorder affecting the nervous system, with an incidence of approximately 1 in 3,000 births. **High-Yield Clinical Pearls for NEET-PG:** * **NF-1 (Chromosome 17):** Clinical triad includes **Café-au-lait spots** (≥6), **Lisch nodules** (iris hamartomas), and **Neurofibromas**. It is also associated with Optic Gliomas and Pheochromocytoma. * **NF-2 (Chromosome 22):** Remember the mnemonic **"22"**—Chromosome **22**, gene **merlin**, and **Bilateral** (2) Acoustic Neuromas [1]. It lacks the Lisch nodules and significant skin manifestations seen in NF-1. * **Diagnostic Tip:** If a question mentions "Juvenile posterior subcapsular lenticular opacities" (cataracts), think **NF-2**. If it mentions "Axillary/Inguinal freckling" (Crowe sign), think **NF-1**.
Question 10: Schizophrenia is a common presentation in which genetic disease?
- A. Down's syndrome
- B. DiGeorge syndrome (Correct Answer)
- C. Klinefelter's syndrome
- D. Neurofibromatosis
Explanation: **Explanation:** **DiGeorge Syndrome (22q11.2 Deletion Syndrome)** is the correct answer because it is one of the strongest known genetic risk factors for developing **Schizophrenia**. Approximately **25-30%** of individuals with this microdeletion develop schizophrenia or schizoaffective disorder in late adolescence or early adulthood. The deletion involves the *COMT* (Catechol-O-methyltransferase) gene, which is crucial for dopamine metabolism; its disruption is thought to contribute to the pathogenesis of psychosis. Schizophrenia is now viewed as a neurodevelopmental disorder, caused by abnormalities of brain development associated with genetic predisposition [1]. **Analysis of Incorrect Options:** * **Down’s Syndrome (Trisomy 21):** While associated with intellectual disability and early-onset **Alzheimer’s disease** (due to the amyloid precursor protein gene on chromosome 21), it is not specifically linked to an increased risk of schizophrenia. * **Klinefelter’s Syndrome (47, XXY):** This is primarily associated with hypogonadism, gynecomastia, and infertility. While there is a slightly higher risk of certain psychiatric issues (like ADHD or anxiety), schizophrenia is not a hallmark presentation. * **Neurofibromatosis (NF1):** This neurocutaneous syndrome is characterized by Lisch nodules, café-au-lait spots, and neurofibromas. While cognitive learning disabilities are common, it is not a classic precursor to schizophrenia. **High-Yield Clinical Pearls for NEET-PG:** * **CATCH-22 Mnemonic for DiGeorge:** **C**ardiac defects (TOF), **A**bnormal facies, **T**hymic hypoplasia (T-cell deficiency), **C**left palate, **H**ypocalcemia (due to parathyroid hypoplasia), and deletion on chromosome **22**. * DiGeorge syndrome results from the failure of the **3rd and 4th pharyngeal pouches** to develop. * Always consider 22q11.2 deletion in a patient with congenital heart disease who later develops psychiatric symptoms.
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