Genetics and Disease — MCQs

Genetics and Disease Indian Medical PG Practice Questions and MCQs

Question 81: A middle-aged man notices that he can no longer fit in his shoes and observes enlargement of his jaw and phalanges. Which hormone mediates these effects?

A. Adrenocorticotropic hormone (ACTH)
B. Thyrotropin-releasing hormone (TRH)
C. Somatomedin (Correct Answer)
D. Transforming growth factor beta (TGF-beta)

Explanation: ### Explanation The clinical presentation of increasing shoe size, jaw enlargement (prognathism), and phalangeal thickening in an adult is classic for **Acromegaly**, which results from the hypersecretion of Growth Hormone (GH) after epiphyseal closure [2]. **Why Somatomedin is Correct:** While GH is the primary hormone secreted by the pituitary adenoma, its peripheral effects—especially linear and bony growth—are mediated by **Somatomedin C**, also known as **Insulin-like Growth Factor 1 (IGF-1)** [1]. GH stimulates the liver to produce IGF-1, which then acts on tissues to promote protein synthesis and skeletal growth [1]. In clinical practice, measuring serum IGF-1 is the most reliable screening test for Acromegaly because it has a longer half-life and lacks the pulsatile secretion pattern of GH [3]. **Why the Other Options are Incorrect:** * **ACTH (A):** Stimulates the adrenal cortex to produce cortisol. Excess leads to Cushing’s syndrome (moon face, buffalo hump), not bony enlargement. * **TRH (B):** A hypothalamic hormone that stimulates the release of TSH and Prolactin. It does not mediate bone or soft tissue growth. * **TGF-beta (D):** A cytokine involved in cell growth, differentiation, and development, but it is not the mediator of GH-induced systemic growth in Acromegaly. **High-Yield Clinical Pearls for NEET-PG:** * **Screening Test:** Serum IGF-1 levels (Somatomedin C). * **Confirmatory Test:** Oral Glucose Tolerance Test (OGTT) with GH measurement [3]. Failure to suppress GH <1 ng/mL after 75g glucose is diagnostic. * **Most Common Cause:** Somatotroph adenoma of the anterior pituitary. * **Radiology:** Look for "spade-like" phalanges on X-ray and enlargement of the sella turcica on MRI. * **Treatment of Choice:** Transsphenoidal surgery [3]. Medical management includes Somatostatin analogues (Octreotide).

Question 82: Which disease is caused by the over-expression of a trinucleotide repeat?

A. Parkinson's disease
B. Caisson's disease
C. Addison's disease
D. Huntington's disease (Correct Answer)

Explanation: ### Explanation **Correct Option: D. Huntington’s Disease** Huntington’s disease (HD) is a classic example of a **Trinucleotide Repeat Expansion** disorder [1]. It is inherited in an **Autosomal Dominant** fashion and is caused by the expansion of the **CAG** (Cytosine-Adenine-Guanine) repeat within the *HTT* gene on chromosome 4. This leads to an abnormally long polyglutamine tract in the huntingtin protein, resulting in toxic gain-of-function that causes neuronal degeneration, particularly in the **caudate nucleus** and putamen [1]. **Analysis of Incorrect Options:** * **A. Parkinson’s Disease:** This is a neurodegenerative movement disorder primarily caused by the loss of dopaminergic neurons in the substantia nigra [1]. While some forms are genetic (e.g., *SNCA*, *LRRK2*, *Parkin* mutations), it is not caused by trinucleotide repeats. * **B. Caisson’s Disease:** Also known as "the bends" or decompression sickness, this is an environmental condition caused by nitrogen bubbles forming in the blood and tissues due to rapid decreases in surrounding pressure (e.g., deep-sea diving). * **C. Addison’s Disease:** This is primary adrenal insufficiency, most commonly caused by autoimmune destruction of the adrenal cortex or infections like Tuberculosis. It is an endocrine disorder, not a trinucleotide repeat expansion. **High-Yield Clinical Pearls for NEET-PG:** * **Anticipation:** HD exhibits "anticipation," where the disease manifests earlier and more severely in successive generations. This is most prominent during **paternal transmission** (spermatogenesis). * **Clinical Triad:** Chorea (involuntary movements), Dementia (cognitive decline), and Psychiatric symptoms (depression/aggression). * **Imaging:** Classic finding on MRI/CT is **atrophy of the caudate nucleus** [2], leading to "boxcar ventricles" (enlargement of the frontal horns of the lateral ventricles). * **Other CAG Repeat Diseases:** Spinocerebellar Ataxias (SCA) and Spinal and Bulbar Muscular Atrophy (Kennedy disease).

Question 83: If both parents are carriers for an autosomal recessive disorder, what are the chances of their offspring being affected?

A. 1 in 4
B. 1 in 2
C. 1 in 3
D. 1 in 1 (Correct Answer)

Explanation: **Explanation** In autosomal recessive (AR) inheritance, a disease manifests only when an individual inherits two copies of the mutated gene (homozygous state). When both parents are **carriers** (heterozygous, Aa), the probability of inheritance for each pregnancy is determined by the Punnett square: * **AA (25%):** Unaffected, non-carrier. * **Aa (50%):** Unaffected, carrier. * **aa (25%):** **Affected.** Therefore, the chance of an offspring being affected is **1 in 4 (25%)**. **Note on the provided answer key:** In standard genetics, the correct answer is **A (1 in 4)**. If the provided key marks **D (1 in 1)** as correct, it is likely a typographical error in the source material or refers to a specific scenario where both parents are *affected* (aa x aa), not carriers. For NEET-PG, always follow the 1:2:1 genotypic ratio for carrier parents. **Analysis of Options:** * **A (1 in 4):** Correct. Represents the 25% probability of inheriting two recessive alleles (aa). * **B (1 in 2):** Incorrect. This represents the probability of an offspring being a **carrier** (50%). * **C (1 in 3):** Incorrect. This is the probability of an **unaffected** child being a carrier (conditional probability). * **D (1 in 1):** Incorrect for carriers. This only occurs if both parents are homozygous affected (aa x aa). **Clinical Pearls for NEET-PG:** 1. **Consanguinity:** Increases the risk of AR disorders by increasing the likelihood that both parents carry the same rare mutation. 2. **Horizontal Transmission:** AR disorders typically appear in a single generation (siblings) rather than every generation. 3. **Common Examples:** Cystic Fibrosis, Sickle Cell Anemia, Thalassemia, and most Inborn Errors of Metabolism (except Hunter Syndrome and Fabry disease, which are X-linked).

Question 84: Which of the following is not an autosomal dominant disorder?

A. Polycystic kidney disease
B. Ehlers-Danlos syndrome
C. Osteogenesis imperfecta
D. Alkaptonuria (Correct Answer)

Explanation: The correct answer is **Alkaptonuria** because it is an **Autosomal Recessive (AR)** disorder, whereas the other options are primarily inherited in an Autosomal Dominant (AD) pattern. **1. Why Alkaptonuria is the correct answer:** Alkaptonuria is a rare metabolic disorder caused by a deficiency of the enzyme **homogentisate 1,2-dioxygenase**. This leads to the accumulation of homogentisic acid. It follows an autosomal recessive inheritance pattern. Clinically, it is characterized by the "classic triad": dark urine (on standing), ochronosis (bluish-black pigmentation of connective tissues), and ochronotic arthritis. **2. Why the other options are incorrect:** * **Polycystic Kidney Disease (PKD):** While there is an AR form (ARPKD), the most common form (90% of cases) is **Autosomal Dominant (ADPKD)**, caused by mutations in *PKD1* or *PKD2* genes. In medical exams, "PKD" without qualification usually refers to the AD form. * **Ehlers-Danlos Syndrome (EDS):** Most common subtypes (like Hypermobile and Classical) follow an **Autosomal Dominant** inheritance, though rare variants can be recessive. * **Osteogenesis Imperfecta (OI):** The majority of cases (Type I-IV), involving mutations in *COL1A1* or *COL1A2*, are inherited as **Autosomal Dominant** traits. **NEET-PG High-Yield Pearls:** * **Mnemonic for AD disorders:** "Very Powerful DOMINANT" (Von Willebrand, Polycystic kidney, Dystrophia myotonica, Osteogenesis imperfecta, Marfan, Intermittent porphyria, Noonan, Achondroplasia, Neurofibromatosis, Tuberous sclerosis). * **Alkaptonuria Diagnosis:** Ferric chloride test (turns urine persistent black) and Benedict’s test (positive for reducing sugars). * **Treatment:** Nitisinone is used to reduce the production of homogentisic acid.

Question 85: Which of the following diseases is NOT caused by a point mutation?

A. Hemochromatosis
B. Achondroplasia
C. Alpha 1 antitrypsin deficiency
D. Hereditary sensory and motor neuropathy type 1 (Correct Answer)

Explanation: ### Explanation The correct answer is **Hereditary Sensory and Motor Neuropathy Type 1 (HSMN-1)**, also known as **Charcot-Marie-Tooth disease type 1A (CMT1A)**. **1. Why HSMN-1 is the correct answer:** Unlike the other options, CMT1A is typically caused by a **large-scale DNA duplication**, not a point mutation. Specifically, it involves a **1.5 Mb duplication** of the **PMP22 gene** on chromosome 17. This leads to an overexpression of the peripheral myelin protein 22, resulting in abnormal myelin structure and function. **2. Why the other options are incorrect:** * **Hemochromatosis:** Most commonly caused by a point mutation in the **HFE gene** (C282Y or H63D), where a single nucleotide change leads to an amino acid substitution [1]. * **Achondroplasia:** This is the most common cause of dwarfism and is caused by a specific point mutation in the **FGFR3 gene** (G380R), leading to a gain-of-function [2]. * **Alpha-1 Antitrypsin Deficiency:** The most severe form (PiZZ) is caused by a single point mutation (Glu342Lys) in the **SERPINA1 gene**, causing protein misfolding and accumulation in the liver [1]. ### NEET-PG Clinical Pearls * **CMT1A (HSMN-1):** Look for "stork leg" or "inverted champagne bottle" appearance of legs, pes cavus, and "onion bulb" formation on nerve biopsy due to repeated demyelination and remyelination. * **Achondroplasia:** 80% of cases are due to *de novo* mutations, often associated with advanced paternal age [2]. * **Point Mutations vs. Repeat Expansions:** Remember that Huntington’s and Fragile X are caused by **trinucleotide repeat expansions**, while CMT1A is a **duplication**. These are high-yield distinctions for "not a point mutation" questions [3].

Question 86: A 22-year-old man presents with arm span greater than height, subluxed lenses, and dilation of the aorta. What is the most likely diagnosis?

A. Ehlers-Danlos syndrome
B. Marfan syndrome (Correct Answer)
C. Werner syndrome
D. Laurence-Moon-Biedl syndrome

Explanation: **Explanation:** The clinical triad of **skeletal abnormalities** (arm span > height), **ectopia lentis** (subluxed lenses), and **aortic root dilation** is the classic presentation of **Marfan Syndrome** [1]. **1. Why Marfan Syndrome is Correct:** Marfan syndrome is an **autosomal dominant** connective tissue disorder caused by a mutation in the **FBN1 gene** on chromosome 15, which encodes **Fibrillin-1** [1]. Fibrillin-1 is essential for the structural integrity of the extracellular matrix and the regulation of TGF-β. * **Skeletal:** Patients exhibit a "marfanoid habitus" (tall stature, arachnodactyly, and an increased arm span-to-height ratio). * **Ocular:** Upward and outward (superotemporal) subluxation of the lens is a hallmark. * **Cardiovascular:** Cystic medial necrosis leads to aortic root dilation, which can progress to aortic dissection—the most common cause of mortality [1]. **2. Why Other Options are Incorrect:** * **Ehlers-Danlos Syndrome:** Characterized by skin hyperextensibility and joint hypermobility. While it involves vascular issues, it typically lacks the tall stature and specific lens subluxation seen here. * **Werner Syndrome:** A rare progeroid (premature aging) syndrome characterized by short stature, cataracts, and skin changes, not marfanoid features. * **Laurence-Moon-Biedl Syndrome:** A ciliopathy presenting with obesity, retinitis pigmentosa, polydactyly, and hypogonadism. **NEET-PG High-Yield Pearls:** * **Lens Subluxation:** Marfan = **Upward** (Superior); Homocystinuria = **Downward** (Interior). * **Diagnosis:** Based on the **Ghent Criteria**. * **Management:** Beta-blockers or ARBs (Losartan) are used to slow the rate of aortic dilation. * **Most common cause of death:** Aortic dissection/rupture [1].

Question 87: Which one of the following conditions is inherited in an autosomal recessive pattern?

A. Homocystinuria (Correct Answer)
B. G6PD deficiency
C. Myotonic dystrophy
D. Otospongiosis

Explanation: **Explanation:** **Homocystinuria (Option A)** is the correct answer. It is an **autosomal recessive (AR)** metabolic disorder, most commonly caused by a deficiency of the enzyme **cystathionine beta-synthase (CBS)**. In NEET-PG, a high-yield rule of thumb is that almost all **inborn errors of metabolism** (enzyme deficiencies) follow an autosomal recessive inheritance pattern [1] (exceptions include Hunter syndrome and Fabry disease). **Analysis of Incorrect Options:** * **G6PD Deficiency (Option B):** This is an **X-linked recessive** condition. It is the most common red cell enzyme deficiency worldwide, leading to episodic hemolysis under oxidative stress. * **Myotonic Dystrophy (Option C):** This follows an **autosomal dominant** pattern. It is characterized by "anticipation" due to CTG trinucleotide repeat expansions on chromosome 19. * **Otospongiosis/Otosclerosis (Option D):** This is typically inherited in an **autosomal dominant** pattern with variable penetrance. It is a common cause of progressive conductive hearing loss in young adults. **Clinical Pearls for NEET-PG:** * **Homocystinuria vs. Marfan Syndrome:** Both present with tall stature and arachnodactyly. However, Homocystinuria features **downward (inferomedial)** lens subluxation, intellectual disability, and a high risk of **thromboembolism**. Marfan syndrome features upward (superotemporal) ectopia lentis and normal intelligence. * **Diagnosis:** Screened via the **Cyanide-nitroprusside test** (positive urine test). * **Treatment:** A subset of patients responds to high doses of **Vitamin B6 (Pyridoxine)**, which acts as a cofactor for the CBS enzyme [2].

Question 88: Which of the following is true in Klinefelter syndrome?

A. Short stature
B. Pituitary adenoma
C. Subnormal intelligence (Correct Answer)
D. Breast adenoma

Explanation: **Explanation:** **Klinefelter Syndrome (47, XXY)** is the most common sex chromosome aneuploidy in males, occurring due to meiotic nondisjunction. **Why Option C is Correct:** While many individuals with Klinefelter syndrome have normal intelligence, there is a statistically significant shift in the IQ distribution. On average, the IQ is 10–15 points lower than siblings [1]. Most patients exhibit **subnormal intelligence** or specific cognitive deficits, particularly in verbal skills, reading, and executive function. The severity of intellectual impairment often correlates with the number of extra X chromosomes (e.g., 48, XXXY is more severe than 47, XXY). **Analysis of Incorrect Options:** * **A. Short stature:** Incorrect. Patients typically have **tall stature** [1] with disproportionately long legs (eunuchoid habitus) due to the extra copy of the *SHOX* gene located on the X chromosome. [1] * **B. Pituitary adenoma:** Incorrect. There is no established association between Klinefelter syndrome and pituitary adenomas. The hormonal profile shows primary testicular failure (hypergonadotropic hypogonadism) [2] with high FSH/LH and low testosterone. [1] * **C. Breast adenoma:** Incorrect. While **gynecomastia** (present in ~50% of cases) is a hallmark, it is a proliferation of glandular tissue, not an adenoma. Notably, these patients have a **20–50 times higher risk of male breast cancer** (carcinoma) compared to the general male population. [2] **High-Yield Clinical Pearls for NEET-PG:** * **Karyotype:** Most common is 47, XXY. * **Testicular Findings:** Small, firm testes (atrophy) with hyalinization and fibrosis of seminiferous tubules. [1] * **Hormonal Profile:** ↓ Testosterone, ↑ LH, ↑ FSH, ↑ Estradiol. [1] * **Associated Risks:** Increased risk of Germ Cell Tumors (specifically mediastinal extragonadal GCTs), Systemic Lupus Erythematosus (SLE), and Osteoporosis. [2]

Question 89: Which one of the following is not a polygenic disorder?

A. Down's syndrome (Correct Answer)
B. Diabetes mellitus
C. Coronary heart disease
D. Congenital heart disease

Explanation: ### Explanation The correct answer is **Down’s syndrome (Option A)**. **1. Why Down’s Syndrome is the Correct Answer:** Down’s syndrome is a **chromosomal disorder**, specifically an aneuploidy characterized by **Trisomy 21**. It is caused by a numerical chromosomal aberration (nondisjunction during meiosis), not by the cumulative effect of multiple genes. Polygenic disorders, by definition, involve the interaction of multiple genes at different loci [1], whereas Down’s syndrome is a single, identifiable cytogenetic abnormality. **2. Why the Other Options are Incorrect:** * **Diabetes Mellitus (Option B):** Type 2 Diabetes is a classic example of a **multifactorial/polygenic disorder**. It results from the complex interaction of multiple susceptibility genes (e.g., TCF7L2) and environmental factors like obesity and sedentary lifestyle [1]. * **Coronary Heart Disease (Option C):** CHD is polygenic, involving various genes regulating lipid metabolism, blood pressure, and inflammation [1]. Its inheritance does not follow a simple Mendelian pattern. * **Congenital Heart Disease (Option D):** While some cases are associated with syndromes (like Down's or DiGeorge), the majority of isolated congenital heart defects (e.g., VSD, ASD) are considered **multifactorial**, involving multiple genetic loci and environmental triggers during cardiogenesis. **3. Clinical Pearls for NEET-PG:** * **Polygenic/Multifactorial Disorders:** These include common "adult-onset" diseases like Hypertension, Schizophrenia, Alzheimer’s, and Psoriasis [1]. They show a "threshold effect" and tend to recur in families. * **Down’s Syndrome High-Yields:** Most common cause is **Meiotic Nondisjunction** (95%), followed by Robertsonian Translocation (4%) and Mosaicism (1%). * **Key Association:** Maternal age is the strongest risk factor for nondisjunction. * **Screening:** Low AFP, low estriol, and high hCG/Inhibin-A (Quadruple marker) are characteristic findings in the second trimester.

Question 90: If a parent is heterozygous and the other parent is homozygous for an autosomal-recessive gene, what will be the genetic outcome for their children?

A. 75% of children will be affected.
B. No child will be affected, but all will be carriers.
C. 50% of children will be affected, and the rest will be carriers. (Correct Answer)
D. 25% of children will be affected, and the rest will be carriers.

Explanation: ### Explanation **1. Understanding the Correct Answer (Option C)** This scenario describes a **"Pseudodominant" inheritance pattern**. In autosomal recessive (AR) inheritance, an individual must inherit two mutant alleles to be affected. * **Parent 1 (Heterozygous):** Genotype **Aa** (Carrier) * **Parent 2 (Homozygous recessive):** Genotype **aa** (Affected) Using a Punnett Square: * **Aa × aa** results in: **Aa, Aa, aa, aa** * **50% Aa:** These children are carriers (phenotypically normal but carry the gene). * **50% aa:** These children are affected. **2. Analysis of Incorrect Options** * **Option A (75%):** This ratio does not occur in standard Mendelian monohybrid crosses for single-gene disorders. * **Option B (0% affected, 100% carriers):** This occurs when one parent is homozygous recessive (**aa**) and the other is homozygous dominant (**AA**). * **Option D (25% affected, 50% carriers):** This is the classic AR ratio when **both** parents are heterozygous carriers (**Aa × Aa**). **3. NEET-PG Clinical Pearls** * **Pseudodominance:** When an AR trait appears in every generation (mimicking Autosomal Dominant inheritance), it usually occurs because an affected individual (**aa**) mates with a carrier (**Aa**). This is common in consanguineous populations or for high-frequency alleles (e.g., Type O blood, Blue eyes). * **Consanguinity:** Increases the risk of AR disorders by increasing the probability that both parents are carriers of the same rare mutant allele. * **Key AR Disorders to Remember:** Cystic Fibrosis, Sickle Cell Anemia, Thalassemia, Phenylketonuria (PKU), and most Inborn Errors of Metabolism (except Hunter Syndrome and Fabry Disease, which are X-linked).

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Principles of Medical Genetics

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Genetic Testing and Counseling

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Chromosomal Disorders

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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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