Genetics and Disease — MCQs

Genetics and Disease Indian Medical PG Practice Questions and MCQs

Question 91: Which of the following disorders is NOT autosomal dominant?

A. Huntington's chorea
B. Neurofibromatosis - 2
C. Tuberous sclerosis
D. Friedreich's ataxia (Correct Answer)

Explanation: **Explanation** The correct answer is **D. Friedreich's ataxia**. **1. Why Friedreich's Ataxia is the Correct Answer:** Friedreich's ataxia is an **Autosomal Recessive (AR)** neurodegenerative disorder [2]. It is caused by a GAA trinucleotide repeat expansion in the *FXN* gene on chromosome 9, which encodes the protein **frataxin**. This leads to mitochondrial iron overload and oxidative stress. Unlike the other options, it requires two copies of the mutated gene for phenotypic expression. **2. Analysis of Incorrect Options (Autosomal Dominant Disorders):** * **Huntington’s Chorea:** An Autosomal Dominant (AD) condition characterized by CAG repeats in the *HTT* gene on chromosome 4 [2]. It exhibits "anticipation," where the disease severity increases in successive generations. * **Neurofibromatosis Type 2 (NF-2):** An AD "phakomatosis" caused by a mutation in the *merlin* gene on chromosome 22. It is classically associated with bilateral acoustic neuromas. * **Tuberous Sclerosis:** An AD multi-system disorder caused by mutations in *TSC1* (hamartin) or *TSC2* (tuberin). It presents with the classic triad of seizures, mental retardation, and adenoma sebaceum. **3. NEET-PG High-Yield Clinical Pearls:** * **Friedreich's Ataxia Triad:** Progressive limb ataxia, absent deep tendon reflexes (DTRs), and extensor plantar responses (Babinski sign). * **Cardiac Involvement:** Hypertrophic cardiomyopathy is the most common cause of death in Friedreich's ataxia. * **Rule of Thumb:** Most structural protein defects are Autosomal Dominant, while most enzyme deficiencies and trinucleotide repeats (except Huntington’s and Myotonic Dystrophy) are Autosomal Recessive [1]. * **Mnemonic for AR:** "Friedreich is a **Recessive** **9**-year-old **GAA**mer" (Recessive, Chromosome 9, GAA repeat).

Question 92: Which of the following is NOT a feature of Wilson's disease?

A. Sunflower Cataract
B. Tremors
C. Pronounced sensory changes (Correct Answer)
D. Renal Calculi may be seen

Explanation: **Explanation:** Wilson’s Disease (Hepatolenticular Degeneration) is an autosomal recessive disorder caused by mutations in the **ATP7B gene**, leading to impaired biliary copper excretion and systemic copper accumulation, primarily in the liver and the basal ganglia [1]. **Why "Pronounced sensory changes" is the correct answer:** Wilson’s disease is primarily a **motor disorder**. Copper deposition occurs predominantly in the basal ganglia (especially the putamen). While it causes significant motor symptoms like tremors, dystonia, and parkinsonism, it **spares the sensory pathways** [1]. The presence of pronounced sensory loss should prompt a clinician to look for alternative diagnoses, such as Vitamin B12 deficiency or multiple sclerosis. **Analysis of Incorrect Options:** * **Sunflower Cataract:** This is a classic ocular sign of copper deposition in the lens. Unlike Kayser-Fleischer (KF) rings (which occur in Descemet's membrane), sunflower cataracts typically do not interfere with vision. * **Tremors:** These are a hallmark neurological manifestation. The most characteristic is the "wing-beating" tremor, though resting or intention tremors are also common [1]. * **Renal Calculi:** Copper toxicity can cause **Fanconi Syndrome** (proximal renal tubular acidosis). This leads to hypercalciuria and hyperphosphaturia, which predisposes patients to the formation of renal stones [1]. **NEET-PG High-Yield Pearls:** * **Screening Test:** Serum Ceruloplasmin (usually <20 mg/dL). * **Gold Standard Diagnosis:** Liver biopsy (showing >250 μg/g dry weight of copper). * **Most Sensitive Ocular Sign:** KF Ring (seen in >98% of neurological cases). * **Treatment:** Chelators (D-Penicillamine, Trientine) or Zinc (blocks intestinal absorption).

Question 93: Which of the following is an autosomal dominant metabolic disorder?

A. Cystic fibrosis
B. Phenylketonuria
C. Alpha-1 antitrypsin deficiency
D. Familial hypercholesterolemia (Correct Answer)

Explanation: The correct answer is **Familial Hypercholesterolemia (FH)**. **1. Why Familial Hypercholesterolemia is correct:** FH is a classic example of an **Autosomal Dominant (AD)** metabolic disorder [1]. It is primarily caused by mutations in the **LDLR gene** (encoding the LDL receptor), though mutations in *APOB* or *PCSK9* can also be responsible [1]. Because it is dominant, even heterozygotes (1 in 250 individuals) have significantly elevated LDL levels from birth, leading to premature atherosclerosis and tendon xanthomas [1]. **2. Why the other options are incorrect:** * **Cystic Fibrosis (A):** This is the most common lethal **Autosomal Recessive (AR)** disorder in Caucasians, caused by mutations in the *CFTR* gene. * **Phenylketonuria (B):** This is an **Autosomal Recessive** inborn error of metabolism involving a deficiency of the enzyme phenylalanine hydroxylase. * **Alpha-1 Antitrypsin Deficiency (C):** This follows an **Autosomal Recessive** (or more accurately, co-dominant) inheritance pattern. It typically presents with early-onset emphysema and liver cirrhosis. **3. NEET-PG High-Yield Pearls:** * **Rule of Thumb:** Most **enzymatic** deficiencies are Autosomal Recessive, whereas disorders involving **structural proteins or receptors** (like the LDL receptor in FH) are often Autosomal Dominant. * **Clinical Triad of FH:** Elevated LDL-C, Tendon Xanthomas (especially the Achilles tendon), and Arcus Senilis at a young age. * **Other AD Metabolic/Structural Disorders to remember:** Marfan Syndrome, Huntington’s Disease, Neurofibromatosis, and Adult Polycystic Kidney Disease (ADPKD).

Question 94: The gene for Wilson's disease is located on which chromosome?

A. Long arm of Chromosome 13 (Correct Answer)
B. Long arm of Chromosome 6
C. Short arm of Chromosome 13
D. Short arm of Chromosome 6

Explanation: **Explanation:** Wilson’s disease (Hepatolenticular degeneration) is an **autosomal recessive** disorder of copper metabolism. The correct answer is **Option A: Long arm of Chromosome 13**. The disease is caused by a mutation in the **ATP7B gene**, which is located on the long arm of chromosome 13 (**13q14.3**). This gene encodes a P-type ATPase membrane protein responsible for transporting copper into the bile and incorporating it into apoceruloplasmin to form ceruloplasmin [3]. A defect in this protein leads to toxic copper accumulation in the liver, brain (basal ganglia), and cornea [1]. **Analysis of Incorrect Options:** * **Option B & D (Chromosome 6):** Chromosome 6 is famously associated with the **HLA complex** (Short arm/6p) and **Hereditary Hemochromatosis** (HFE gene on 6p21.3) [2]. It is not related to copper metabolism. * **Option C (Short arm of Chromosome 13):** While the chromosome number is correct, the ATP7B gene is specifically localized to the **long arm (q)**, not the short arm (p). **High-Yield Clinical Pearls for NEET-PG:** * **Diagnosis:** The most sensitive screening test is **decreased serum ceruloplasmin** (<20 mg/dL) [3]. The gold standard for diagnosis is increased **liver copper content** on biopsy (>250 μg/g dry weight). * **Ocular Finding:** **Kayser-Fleischer (KF) rings** (copper deposition in Descemet’s membrane) are seen in 95% of patients with neurological symptoms. * **Treatment:** Drug of choice is **Chelation therapy** (D-Penicillamine or Trientine). Zinc is used for maintenance as it interferes with intestinal copper absorption. * **Neurology:** Characterized by "Wing-beating" tremors and "Panda sign" on MRI brain [1].

Question 95: A normal couple has one daughter affected with Cystic fibrosis. They are now planning to have another child. What is the chance of siblings being affected by the disease?

A. 0%
B. 50%
C. 25% (Correct Answer)
D. 75%

Explanation: **Explanation:** **1. Understanding the Correct Answer (C):** Cystic Fibrosis (CF) is an **Autosomal Recessive (AR)** disorder. For a "normal" couple to have an affected child, both parents must be asymptomatic **obligate carriers** (genotype: **Aa**). According to Mendelian inheritance, when two carriers (Aa x Aa) conceive [1]: * 25% chance of an affected child (**aa**) * 50% chance of a carrier child (**Aa**) * 25% chance of a genetically normal child (**AA**) Therefore, for every subsequent pregnancy, there is a **25% (1 in 4)** risk of the sibling being affected. **2. Why Other Options are Incorrect:** * **A (0%):** This would only occur if at least one parent was homozygous dominant (AA) and not a carrier. * **B (50%):** This risk is associated with **Autosomal Dominant** conditions (if one parent is affected) or the risk of being a **carrier** in an AR condition. * **D (75%):** This represents the probability of a child being **unaffected** (Normal + Carrier) in an AR cross. **3. Clinical Pearls for NEET-PG:** * **Most common mutation:** ΔF508 on Chromosome 7 (CFTR gene) [2]. * **Diagnosis:** Sweat Chloride test (>60 mEq/L) is the gold standard [1]. * **Key Associations:** Meconium ileus (newborns), Bilateral Absence of Vas Deferens (infertility in males), and recurrent *Pseudomonas* infections [2]. * **Rule of Thumb:** In AR pedigrees, if the parents are normal but a child is affected, always assume both parents are carriers (25% recurrence risk) [1]. If an unaffected sibling of an affected child asks about their carrier status, the probability is **2/3** (since the 'aa' possibility is already ruled out) [1].

Question 96: Which of the following is an example of non-Mendelian inheritance?

A. Genomic imprinting
B. Uniparental disomy
C. Mitochondrial inheritance
D. All of the above (Correct Answer)

Explanation: Mendelian inheritance follows the laws of segregation and independent assortment, where traits are determined by nuclear genes inherited equally from both parents. **Non-Mendelian inheritance** refers to patterns of inheritance that deviate from these rules due to epigenetic modifications, extranuclear DNA, or chromosomal abnormalities. 1. **Genomic Imprinting (Option A):** This involves the functional silencing of a gene depending on which parent it is inherited from. It is mediated by DNA methylation. Classic examples include **Prader-Willi Syndrome** (paternal deletion/maternal imprinting) and **Angelman Syndrome** (maternal deletion/paternal imprinting) on chromosome 15 [1]. 2. **Uniparental Disomy (Option B):** This occurs when an individual receives two copies of a chromosome from one parent and zero copies from the other [1]. This violates the Mendelian principle of biparental inheritance and can lead to disease if the involved region contains imprinted genes. 3. **Mitochondrial Inheritance (Option C):** Also known as maternal inheritance, this involves DNA located in the mitochondria rather than the nucleus [2]. Since only the ovum contributes mitochondria to the zygote, these diseases (e.g., **MELAS, LHON**) are passed from mother to all children, but never from the father. **Clinical Pearls for NEET-PG:** * **Anticipation:** A form of non-Mendelian inheritance seen in Trinucleotide Repeat Disorders (e.g., Huntington’s, Fragile X) where the disease severity increases in successive generations. * **Heteroplasmy:** The presence of a mixture of more than one type of organellar genome (normal and mutated mitochondrial DNA) within a cell, explaining the variable clinical expression of mitochondrial diseases. * **Germline Mosaicism:** When a mutation occurs in the gonads of a phenotypically normal parent, leading to affected offspring (common in Osteogenesis Imperfecta).

Question 97: Which of the following inherited disorders is the most common?

A. Wilson's Disease
B. Antitrypsin deficiency
C. Cystic fibrosis
D. Hemochromatosis (Correct Answer)

Explanation: The correct answer is **Hemochromatosis**. In the context of medical genetics, "most common" refers to the prevalence of the genetic mutation within a specific population (typically Caucasians for these standardized exams). **1. Why Hemochromatosis is correct:** Hereditary Hemochromatosis (HH), specifically the **HFE gene mutation (C282Y)**, is the most common autosomal recessive disorder in Caucasians of Northern European descent [2]. The carrier frequency is approximately **1 in 10**, and the disease prevalence is about **1 in 200 to 1 in 500**. Although it has low penetrance (not everyone with the genotype shows symptoms), it remains the most frequent inherited metabolic disorder [2]. Both the C282Y and the H63D mutations can be identified by genetic testing [1]. **2. Why the other options are incorrect:** * **Cystic Fibrosis:** While it is the most common *lethal* genetic disease in Caucasians, its prevalence is approximately **1 in 2,500 to 3,000**, making it less frequent than Hemochromatosis. * **Alpha-1 Antitrypsin Deficiency:** This is also common (prevalence ~1 in 2,500), but it ranks behind Hemochromatosis in overall frequency. * **Wilson’s Disease:** This is relatively rare, with a worldwide prevalence of approximately **1 in 30,000**. **Clinical Pearls for NEET-PG:** * **Hemochromatosis Triad:** "Bronze diabetes" (Skin hyperpigmentation, Diabetes Mellitus, and Cirrhosis) [2]. * **Screening:** The most sensitive initial test is **Transferrin Saturation** (>45%); the most accurate non-invasive test is MRI (quantifying hepatic iron) [1]. * **Treatment:** The mainstay of treatment is **Therapeutic Phlebotomy**, aiming for a serum ferritin level of 50–100 ng/mL [1]. * **Association:** HH is associated with an increased risk of *Vibrio vulnificus* and *Listeria* infections due to iron overload.

Question 98: Edwards syndrome is associated with which chromosomal abnormality?

A. Trisomy 21
B. Trisomy 18 (Correct Answer)
C. Trisomy 13
D. 5p deletion

Explanation: **Explanation:** **Edwards syndrome** is caused by **Trisomy 18** (an extra copy of chromosome 18). It is the second most common autosomal trisomy among live births, following Down syndrome. The condition is characterized by severe intellectual disability and multi-system defects, with a high mortality rate in the first year of life. **Analysis of Options:** * **Option A (Trisomy 21):** This is **Down syndrome**, the most common chromosomal disorder. Key features include Brushfield spots, simian crease, and increased risk of Alzheimer’s and ALL. * **Option C (Trisomy 13):** This is **Patau syndrome**. It is clinically distinguished by "midline defects" such as holoprosencephaly, cleft lip/palate, and polydactyly. * **Option D (5p deletion):** This is **Cri-du-chat syndrome**. It is characterized by a high-pitched, cat-like cry, microcephaly, and severe developmental delay. **Clinical Pearls for NEET-PG:** To differentiate the trisomies quickly, remember these high-yield physical findings for Edwards syndrome: 1. **Clenched fists** with overlapping fingers (index finger over 3rd, 5th over 4th). 2. **Rocker-bottom feet** (also seen in Patau, but classic for Edwards). 3. **Micrognathia** (small jaw) and low-set malformed ears. 4. **Congenital Heart Disease:** Most commonly VSD or PDA. 5. **Prenatal Screening:** Shows decreased levels of MS-AFP, hCG, and unconjugated estriol (uE3). **Mnemonic:** "Edwards" starts with **E**, and **E**ighteen starts with **E**. Also, think of **E**lection age (18) to remember Trisomy 18.

Question 99: In addition to neurofibromatosis, what other examination finding would you expect for this patient?

A. Aortic regurgitation
B. Chvostek sign
C. Lisch nodules (Correct Answer)
D. Thyroid bruit

Explanation: ***Lisch nodules*** - **Lisch nodules** are **iris hamartomas** that appear as well-defined, dome-shaped, tan to brown nodules on the iris surface, present in over **90% of adults** with **neurofibromatosis type 1 (NF1)**. - These **benign melanocytic hamartomas** are pathognomonic for **NF1** and increase in number with age, making them a key diagnostic criterion for the condition. *Aortic regurgitation* - **Aortic regurgitation** is not a recognized feature of **neurofibromatosis type 1** and would suggest other conditions like **bicuspid aortic valve** or **rheumatic heart disease**. - **NF1** primarily affects the **nervous system**, **skin**, and **bones**, not typically causing significant **cardiac valve abnormalities**. *Chvostek sign* - **Chvostek sign** is a clinical sign of **hypocalcemia** where tapping the **facial nerve** causes **facial muscle twitching**, unrelated to **neurofibromatosis**. - This sign indicates **neuromuscular irritability** due to **low calcium levels** and has no association with the **genetic mutations** seen in **NF1**. *Thyroid bruit* - **Thyroid bruit** is associated with **hyperthyroidism** (especially **Graves' disease**) due to increased **thyroid vascularity** and blood flow. - **Neurofibromatosis type 1** does not typically cause **thyroid dysfunction** or **thyroid enlargement** that would produce an audible bruit.

Question 100: Absent radius is seen in all conditions except which of the following?

A. Holt-Oram syndrome
B. Fanconi anemia
C. Trisomy 13
D. Ectodermal dysplasia (Correct Answer)

Explanation: Explanation: The correct answer is Ectodermal dysplasia. This condition is a group of disorders characterized by abnormalities in tissues derived from the embryonic ectoderm, primarily affecting the hair, teeth, nails, and sweat glands (e.g., hypodontia, anhidrosis, and hypotrichosis). It does not typically involve limb reduction defects like radial aplasia. Analysis of Options: * Holt-Oram Syndrome: Also known as "Heart-Hand Syndrome," it is characterized by radial ray defects (absent or hypoplastic radius/thumb) and congenital cardiac defects (most commonly Secundum ASD). * Fanconi Anemia: This is the most common inherited bone marrow failure syndrome. It frequently presents with skeletal anomalies, specifically involving the radial ray (absent radius or bifid thumb), along with cafe-au-lait spots and short stature. * Trisomy 13 (Patau Syndrome): This chromosomal anomaly presents with a constellation of defects including polydactyly, microcephaly, cleft lip/palate, and occasionally radial hypoplasia or aplasia. Clinical Pearls for NEET-PG: To remember conditions associated with Radial Ray Defects, use the mnemonic "FAR VACTERL": 1. Fanconi Anemia 2. Amniotic Band Syndrome 3. Radius-Platelet Syndrome (TAR Syndrome - Note: Thumb is present in TAR) 4. VACTERL association (Vertebral, Anal, Cardiac, TEF, Renal, Limb) 5. Holt-Oram Syndrome 6. Trisomy 18 (Edwards) and Trisomy 13 (Patau) High-yield distinction: In TAR (Thrombocytopenia Absent Radius) syndrome, the radius is absent but the thumb is always present, which distinguishes it from Fanconi anemia and Holt-Oram where the thumb is usually absent.

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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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