Genetics and Disease — MCQs

Genetics and Disease Indian Medical PG Practice Questions and MCQs

Question 171: Which investigation is used to diagnose Edward syndrome?

A. Karyotype
B. FISH (Correct Answer)
C. MLPA
D. Microarray

Explanation: **Explanation:** **Edward Syndrome (Trisomy 18)** is a chromosomal aneuploidy characterized by an extra copy of chromosome 18. **Why FISH is the Correct Answer:** **Fluorescence In Situ Hybridization (FISH)** is the preferred rapid diagnostic tool for common aneuploidies (Trisomies 13, 18, 21) [1]. It uses fluorescent probes that bind to specific DNA sequences on chromosome 18. Its primary advantage in a clinical/exam setting is **speed**; it provides results within 24–48 hours without requiring cell culture, making it the standard for rapid prenatal or postnatal confirmation of suspected Edward syndrome [1]. **Analysis of Incorrect Options:** * **Karyotype:** While Karyotyping is the "Gold Standard" for definitive diagnosis as it visualizes the entire genome and identifies translocations, it requires living cells and a long culture period (1–2 weeks). In many MCQ contexts, if a rapid or specific probe-based diagnosis is implied, FISH is prioritized. * **MLPA (Multiplex Ligation-dependent Probe Amplification):** This is a PCR-based method used to detect copy number variations. While effective, it is less commonly used as the primary bedside diagnostic tool compared to FISH for trisomies. * **Microarray (CMA):** Chromosomal Microarray is superior for detecting submicroscopic deletions or duplications (microdeletions). However, it is expensive and unnecessary for a full trisomy like Edward syndrome, which is easily seen on FISH. **High-Yield Clinical Pearls for NEET-PG:** * **Karyotype:** 47, XX/XY, +18. * **Clinical Triad:** Clenched fists with overlapping fingers, Rocker-bottom feet, and Micrognathia. * **Cardiac Defect:** VSD (most common) and PDA. * **Prognosis:** Most die within the first year of life. * **Screening:** On Quadruple screen, **all markers are decreased** (AFP, uE3, hCG, and Inhibin A).

Question 172: Werner disease is associated with?

A. Intestinal polyps
B. Multiple cancers
C. Lax joints
D. Premature ageing (Correct Answer)

Explanation: **Explanation:** **Werner Syndrome (Adult Progeria)** is an autosomal recessive disorder characterized by **premature aging**. It is caused by a mutation in the **WRN gene** (located on chromosome 8), which encodes a DNA helicase essential for DNA repair, replication, and maintaining telomere stability [1]. The loss of this enzyme leads to rapid accumulation of DNA damage and genomic instability. * **Why Premature Ageing is Correct:** Patients typically appear normal until puberty, after which they rapidly develop features of old age. Key clinical signs include graying and loss of hair, bilateral cataracts (usually by age 30), scleroderma-like skin changes, osteoporosis, and atherosclerosis. * **Why other options are incorrect:** * **Intestinal polyps:** This is characteristic of syndromes like Peutz-Jeghers or Familial Adenomatous Polyposis (FAP), not Werner syndrome. * **Multiple cancers:** While Werner syndrome patients have an increased risk of specific rare malignancies (like soft tissue sarcomas or osteosarcoma), "Multiple cancers" is the hallmark of **Li-Fraumeni syndrome** (TP53 mutation). * **Lax joints:** This is a feature of connective tissue disorders like **Ehlers-Danlos syndrome**. In contrast, Werner syndrome often presents with joint stiffness and skin tightening. **High-Yield Clinical Pearls for NEET-PG:** * **Gene:** WRN Gene (8p12); Protein: RecQ Helicase family. * **Classic Presentation:** "Bird-like" facies, short stature, high-pitched voice, and early-onset Type 2 Diabetes Mellitus. * **Most common cause of death:** Myocardial infarction (due to accelerated atherosclerosis) or malignancy. * **Differential:** **Hutchinson-Gilford Syndrome** is "Infantile Progeria" (LMNA gene), where aging begins in early childhood, unlike Werner which begins at puberty [1].

Question 173: A 32-year-old man presents for routine evaluation. He has no symptoms but has noticed some new "nodules" on his legs. Physical examination reveals lumps on his Achilles tendon, yellow lesions around his eyes, and pigmentation of his iris. Which of the following is the most likely diagnosis?

A. Familial hyperlipidemia (Correct Answer)
B. Diabetes
C. Myxedema
D. Chronic renal disease

Explanation: **Explanation:** The clinical presentation described is a classic constellation of signs pointing toward **Familial Hyperlipidemia (specifically Type IIa/Familial Hypercholesterolemia)**. The "nodules" on the Achilles tendon are **tendon xanthomas**, which are pathognomonic for high levels of LDL cholesterol [1]. The yellow lesions around the eyes are **xanthelasmas**, and the iris pigmentation (likely referring to **corneal arcus** or arcus senilis in a young patient) further confirms a systemic lipid deposition disorder. **Analysis of Options:** * **A. Familial Hyperlipidemia (Correct):** This autosomal dominant condition involves a defect in the LDL receptor [1]. The hallmark is severely elevated LDL, leading to premature atherosclerosis and lipid deposits in tendons (xanthomas) and skin (xanthelasma). * **B. Diabetes:** While diabetes can cause skin changes (like necrobiosis lipoidica or acanthosis nigricans), it does not typically cause tendon xanthomas. * **C. Myxedema (Hypothyroidism):** Hypothyroidism can cause secondary hyperlipidemia and xanthelasma, but it is usually accompanied by systemic symptoms like weight gain, cold intolerance, and bradycardia, which are absent here. * **D. Chronic Renal Disease:** This can lead to secondary dyslipidemia (Type IV), but it typically presents with elevated triglycerides rather than the isolated severe hypercholesterolemia required to form tendon xanthomas. **High-Yield Clinical Pearls for NEET-PG:** * **Tendon Xanthomas:** Most commonly involve the **Achilles tendon**, followed by the extensor tendons of the hands. * **Eruptive Xanthomas:** Small, itchy yellow papules on the buttocks/extensors; associated with **Hypertriglyceridemia** (Types I, IV, V). * **Palmar Xanthomas:** Yellow streaks in palmar creases; pathognomonic for **Type III Hyperlipoproteinemia** (Dysbetalipoproteinemia). * **Corneal Arcus:** Significant if seen in a patient **<45 years old** (Arcus juvenilis), suggesting underlying Familial Hypercholesterolemia.

Question 174: In a patient with cystic fibrosis presenting with high fever and productive cough, what is the most common causative organism?

A. Pseudomonas aeruginosa (Correct Answer)
B. Haemophilus influenzae
C. Staphylococcus aureus
D. Streptococcus species

Explanation: **Explanation:** The correct answer is **Pseudomonas aeruginosa**. Cystic Fibrosis (CF) is characterized by defective chloride transport (CFTR gene mutation), leading to thick, inspissated mucus that impairs mucociliary clearance [1]. This creates a niche for chronic bacterial colonization. While various pathogens affect CF patients, **Pseudomonas aeruginosa** is the most common causative organism overall, particularly in adults, and is the leading cause of progressive lung function decline and mortality. **Analysis of Options:** * **A. Pseudomonas aeruginosa:** It is the most prevalent pathogen in the CF population (found in ~60-80% of adults). It often undergoes a phenotypic switch to a "mucoid" variant (alginate production), which forms biofilms, making it highly resistant to antibiotics and immune clearance. * **B. Haemophilus influenzae:** This is a common pathogen in the early childhood stages of CF but is typically superseded by *S. aureus* and *Pseudomonas* as the patient ages. * **C. Staphylococcus aureus:** This is the **most common organism in infants and young children** with CF. However, across the entire lifespan and in the context of chronic colonization, *Pseudomonas* remains the dominant answer for "most common." * **D. Streptococcus species:** While *S. pneumoniae* can cause pneumonia in CF patients, it is not the characteristic or most frequent pathogen associated with the disease's pathophysiology. **NEET-PG High-Yield Pearls:** * **Age-specific prevalence:** *S. aureus* is #1 in children (<10-15 years); *P. aeruginosa* is #1 in adults. * **Burkholderia cepacia complex:** Associated with "Cepacia syndrome" (rapid clinical decline) and is often a contraindication for lung transplantation. * **Treatment:** Anti-pseudomonal coverage usually requires two drugs from different classes (e.g., Ceftazidime/Piperacillin-Tazobactam + Tobramycin). * **Diagnosis:** Sweat chloride test >60 mEq/L remains the gold standard.

Question 175: Which of the following is an example of a single gene disorder?

A. Duchenne muscular dystrophy (Correct Answer)
B. Down syndrome
C. Turner syndrome
D. Klinefelter syndrome

Explanation: ### Explanation **Correct Option: A. Duchenne muscular dystrophy (DMD)** Duchenne muscular dystrophy is a classic example of a **single gene disorder** (Mendelian disorder) [1]. It is caused by a mutation in a specific gene—the **DMD gene** located on the X chromosome (Xp21)—which encodes the protein **dystrophin**. Because the disease results from a defect in one specific locus, it follows predictable patterns of inheritance (X-linked recessive). **Incorrect Options:** * **B, C, and D (Down, Turner, and Klinefelter syndromes):** These are **chromosomal disorders** (aneuploidies), not single gene disorders. They result from an abnormal number of chromosomes (numerical aberrations) rather than a mutation within a single gene. * **Down syndrome:** Trisomy 21 (47, XX/XY +21). * **Turner syndrome:** Monosomy X (45, XO). * **Klinefelter syndrome:** Extra X chromosome in males (47, XXY). **High-Yield Clinical Pearls for NEET-PG:** * **DMD Gene:** It is the **largest known human gene**, making it highly susceptible to spontaneous mutations. * **Inheritance:** X-linked recessive; therefore, it primarily affects males while females are typically asymptomatic carriers [1]. * **Clinical Signs:** Look for **Gowers' sign** (using hands to "climb up" the legs to stand) and **pseudohypertrophy of the calves** (fatty replacement of muscle). * **Diagnosis:** Elevated Serum Creatine Kinase (CK) levels are seen early; Genetic testing is the gold standard, but muscle biopsy shows absent dystrophin. * **Death:** Usually occurs in the second decade due to respiratory failure or dilated cardiomyopathy [1].

Question 176: A 20-year-old female on oral contraceptive pills presents with behavioral changes and abdominal pain. What is the most probable diagnosis?

A. Pancreatitis
B. Aortic aneurysm
C. Systemic Lupus Erythematosus (SLE)
D. Acute intermittent porphyria (Correct Answer)

Explanation: The clinical presentation of **Acute Intermittent Porphyria (AIP)** is classically described by the "5 Ps": **P**ainful abdomen, **P**sychological disturbances (behavioral changes), **P**olyneuropathy, **P**urple urine, and **P**recipitated by drugs [1]. **Why AIP is the correct answer:** AIP is an autosomal dominant metabolic disorder caused by a deficiency of the enzyme **Porphobilinogen (PBG) deaminase**. The symptoms are triggered by factors that induce the enzyme **ALA synthase**, leading to an accumulation of toxic heme precursors (ALA and PBG). **Oral Contraceptive Pills (OCPs)**, specifically the progesterone component, are potent inducers of the cytochrome P450 system and ALA synthase, making them a classic trigger for acute attacks in susceptible females [1]. **Why other options are incorrect:** * **Pancreatitis:** While it causes severe abdominal pain, it is not typically associated with acute behavioral changes or triggered specifically by OCPs (unless OCP-induced hypertriglyceridemia is present, which is less common in a 20-year-old). * **Aortic Aneurysm:** Extremely rare in a 20-year-old female and does not explain the psychiatric symptoms. * **SLE:** While SLE can cause abdominal pain (vasculitis) and psychosis (lupus cerebritis), the acute onset triggered by OCPs more specifically points toward a metabolic porphyric crisis. **High-Yield Clinical Pearls for NEET-PG:** * **Diagnosis:** Elevated urinary **PBG** levels during an attack (Screening: Hoesch test/Watson-Schwartz test). * **Management:** Intravenous **Hemin** (suppresses ALA synthase) and **10% Dextrose** (glucose inhibits ALA synthase). * **Key Trigger Drugs:** Barbiturates, Sulfonamides, Griseofulvin, and Alcohol. * **Note:** Unlike other porphyrias, AIP has **no cutaneous manifestations** (no photosensitivity).

Question 177: Which of the following conditions is inherited in an autosomal recessive pattern?

A. Achondroplasia
B. Duchenne muscular dystrophy
C. Thalassemia (Correct Answer)
D. Marfan's syndrome

Explanation: **Explanation:** **Thalassemia** is the correct answer because it follows an **Autosomal Recessive (AR)** inheritance pattern. This means an individual must inherit two defective globin genes (one from each parent) to manifest the disease. In Thalassemia, there is a quantitative deficiency in the synthesis of hemoglobin chains (alpha or beta), leading to microcytic hypochromic anemia [1]. **Analysis of Incorrect Options:** * **Achondroplasia:** This is the most common cause of short-limb dwarfism [2] and is inherited in an **Autosomal Dominant (AD)** pattern. It is primarily caused by a gain-of-function mutation in the *FGFR3* gene. * **Duchenne Muscular Dystrophy (DMD):** This is an **X-linked Recessive** disorder. It involves a mutation in the *Dystrophin* gene, primarily affecting males, while females typically act as asymptomatic carriers. * **Marfan’s Syndrome:** This is an **Autosomal Dominant (AD)** connective tissue disorder caused by mutations in the *FBN1* gene on chromosome 15, which encodes the protein fibrillin-1. **NEET-PG High-Yield Pearls:** * **AR Mnemonic:** Most enzyme deficiencies and hemoglobinopathies (Sickle Cell, Thalassemia) are AR. Exceptions include Hunter syndrome and Fabry disease (X-linked). * **AD Mnemonic:** Most structural protein defects (Marfan’s, Achondroplasia, Osteogenesis Imperfecta) are AD. * **Thalassemia Screening:** The **NESTROFT** (Naked Eye Single Tube Red Cell Osmotic Fragility Test) is a common screening tool, but **Hb Electrophoresis** (showing elevated HbA2 >3.5%) is the gold standard for diagnosing Beta-Thalassemia trait.

Question 178: Which of the following is NOT a disease caused by trinucleotide repeats?

A. Huntington's chorea
B. Myotonic dystrophy
C. Friedreich's ataxia
D. Hereditary Nonpolyposis Colon Cancer (Correct Answer)

Explanation: ### Explanation The correct answer is **D. Hereditary Nonpolyposis Colon Cancer (HNPCC)**. **1. Why HNPCC is the correct answer:** Hereditary Nonpolyposis Colon Cancer (also known as Lynch Syndrome) is caused by mutations in **DNA Mismatch Repair (MMR) genes** (most commonly *MLH1, MSH2, MSH6,* and *PMS2*) [1]. This leads to **microsatellite instability (MSI)**, which involves changes in the length of short, repeated DNA sequences [1]. However, it is not classified as a "trinucleotide repeat expansion disorder," which involves a specific mechanism of dynamic mutations where the number of repeats increases across generations (anticipation). **2. Why the other options are incorrect:** * **Huntington’s Chorea:** Caused by a **CAG** repeat expansion in the *HTT* gene on chromosome 4. It is an autosomal dominant neurodegenerative disorder. * **Myotonic Dystrophy (Type 1):** Caused by a **CTG** repeat expansion in the *DMPK* gene on chromosome 19. It is the most common adult-onset muscular dystrophy. * **Friedreich’s Ataxia:** Caused by a **GAA** repeat expansion in the *FXN* gene (encoding Frataxin) on chromosome 9. Notably, it is the only common trinucleotide repeat disorder that is **autosomal recessive**. **3. NEET-PG High-Yield Clinical Pearls:** * **Anticipation:** This is the hallmark of trinucleotide repeat disorders, where the disease manifests at an earlier age and with increased severity in successive generations. * **Location of Repeats:** * **Exonic (Coding):** Huntington’s (CAG). * **Intronic (Non-coding):** Friedreich’s Ataxia (GAA). * **Untranslated Regions (UTR):** Fragile X (CGG in 5' UTR) and Myotonic Dystrophy (CTG in 3' UTR). * **Mnemonic for HNPCC:** Remember "Mismatch Repair" for Lynch Syndrome, not "Repeat Expansion."

Question 179: In familial Mediterranean fever, which protein-encoding gene undergoes mutation?

A. Pyrin (Correct Answer)
B. Perforin
C. Atrial natriuretic factor
D. Immunoglobulin light chain

Explanation: **Explanation:** **Familial Mediterranean Fever (FMF)** is an autosomal recessive autoinflammatory disorder characterized by recurrent episodes of fever and serositis (peritonitis, pleuritis, or synovitis). 1. **Why Pyrin is Correct:** The disease is caused by mutations in the **MEFV gene** (located on chromosome 16), which encodes the protein **Pyrin**. Pyrin is primarily expressed in neutrophils and is a key component of the inflammasome complex. Under normal conditions, pyrin regulates the inflammatory response; however, mutations lead to the uncontrolled activation of **Interleukin-1̠ (IL-1̠)**, resulting in the characteristic paroxysms of systemic inflammation. 2. **Why Other Options are Incorrect:** * **Perforin:** Mutations in the *PRF1* gene (encoding perforin) are associated with **Familial Hemophagocytic Lymphohistiocytosis (HLH)**, not FMF. * **Atrial Natriuretic Factor (ANF):** This is associated with **Isolated Atrial Amyloidosis**. * **Immunoglobulin Light Chain:** This is the precursor protein for **AL Amyloidosis**, typically seen in plasma cell dyscrasias like Multiple Myeloma. **High-Yield Clinical Pearls for NEET-PG:** * **Amyloidosis:** The most dreaded complication of untreated FMF is **AA Amyloidosis** (Secondary Amyloidosis), which often leads to nephrotic syndrome and renal failure [1]. * **Drug of Choice:** **Colchicine** is the mainstay of treatment. It prevents acute attacks and, more importantly, prevents the development of AA amyloidosis. * **Clinical Presentation:** Look for a patient of Mediterranean descent with "sterile peritonitis" (mimicking appendicitis) and a positive family history.

Question 180: All of the following have autosomal dominant pattern of inheritance except?

A. Huntington's chorea
B. Hemophilia A (Correct Answer)
C. Tuberous sclerosis
D. Marfan's syndrome

Explanation: The correct answer is **Hemophilia A** because it follows an **X-linked recessive (XLR)** pattern of inheritance, not autosomal dominant. 1. **Hemophilia A (Option B):** This is caused by a deficiency of Factor VIII. The gene is located on the X chromosome [2]. Therefore, it primarily affects males, while females are typically asymptomatic carriers. A father cannot pass the disease to his son, which is a hallmark of X-linked inheritance. 2. **Huntington’s Chorea (Option A):** This is a classic **Autosomal Dominant (AD)** neurodegenerative disorder caused by CAG trinucleotide repeats on Chromosome 4. It exhibits "anticipation," where the disease manifests earlier in successive generations. 3. **Tuberous Sclerosis (Option C):** This is an **AD** neurocutaneous syndrome (phakomatosis) caused by mutations in the *TSC1* (hamartin) or *TSC2* (tuberin) genes. It is characterized by the development of benign tumors (hamartomas) in multiple organs. 4. **Marfan’s Syndrome (Option D):** This is an **AD** connective tissue disorder caused by a mutation in the *FBN1* gene on Chromosome 15 [1], leading to defective fibrillin-1. **NEET-PG High-Yield Pearls:** * **Mnemonic for AD disorders:** "**V**ery **P**owerful **M**nemonic **H**elps **A**ll **D**octors" (**V**on Willebrand, **P**olycystic Kidney, **M**arfan/**M**yotonic dystrophy, **H**untington/**H**ereditary Spherocytosis, **A**chondroplasia, **D**ystrophia Myotonica). * **Hemophilia A vs. B:** Both are XLR. Hemophilia A = Factor VIII deficiency; Hemophilia B (Christmas Disease) = Factor IX deficiency [2]. * **Vertical Transmission:** AD disorders typically show vertical transmission (seen in every generation), whereas XLR disorders often skip generations via carrier females.

Practice by Chapter

Principles of Medical Genetics

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Genetic Testing and Counseling

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Single Gene Disorders

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Chromosomal Disorders

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Mitochondrial Diseases

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Pharmacogenomics

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Cancer Genetics

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Genetics of Common Diseases

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Epigenetics and Disease

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Genetic Basis of Developmental Disorders

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Ethical Issues in Medical Genetics

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Gene Therapy and Precision Medicine

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