Genetics and Disease — MCQs

Genetics and Disease Indian Medical PG Practice Questions and MCQs

Question 11: The following pedigree represents which of the following genetic disorders?

A. Osteogenesis imperfecta (Correct Answer)
B. Wilson’s disease
C. Alkaptonuria
D. Cystic fibrosis

Explanation: ***Osteogenesis imperfecta*** - Shows **autosomal dominant inheritance** pattern with **vertical transmission** - affected individuals in every generation passing the condition to approximately **50% of their offspring**. - **Type I osteogenesis imperfecta** is the most common form with this inheritance pattern, caused by mutations in **COL1A1** or **COL1A2** genes affecting collagen production. *Wilson's disease* - Follows **autosomal recessive inheritance** pattern, which would show **horizontal transmission** with unaffected parents having affected children. - Caused by mutations in the **ATP7B gene**, leading to copper accumulation, and would not demonstrate the vertical inheritance pattern seen in this pedigree. *Alkaptonuria* - Exhibits **autosomal recessive inheritance**, characterized by **consanguineous marriages** and affected siblings from unaffected parents. - Results from **homogentisic acid oxidase deficiency**, causing dark urine and would not show the dominant inheritance pattern observed. *Cystic fibrosis* - Demonstrates **autosomal recessive inheritance** with **horizontal transmission** pattern, typically affecting siblings rather than successive generations. - Caused by **CFTR gene mutations** and would require both parents to be carriers, not the dominant pattern shown in this pedigree.

Question 12: Which of the following statements is TRUE regarding Duchenne muscular dystrophy?

A. It is autosomal dominant.
B. It has an onset in the second decade of life.
C. There is a universal increase in creatine kinase. (Correct Answer)
D. Cardiac muscle fibers are normal.

Explanation: **Explanation:** **Duchenne Muscular Dystrophy (DMD)** is the most common and severe form of muscular dystrophy, caused by a mutation in the *DMD* gene on the X chromosome, leading to a complete absence of the protein **dystrophin**. 1. **Why Option C is Correct:** In DMD, the absence of dystrophin leads to membrane instability and chronic muscle fiber necrosis. This results in a **universal and massive elevation of Serum Creatine Kinase (CK)**, often 50 to 100 times the upper limit of normal. This elevation is present from birth, even in the asymptomatic stage, making it a highly sensitive screening marker. 2. **Why Other Options are Incorrect:** * **Option A:** DMD follows an **X-linked recessive** inheritance pattern, not autosomal dominant. It primarily affects males, while females are typically asymptomatic carriers. * **Option B:** The onset is in **early childhood (usually 3–5 years)**. Patients typically become wheelchair-bound by age 12. Onset in the second decade is more characteristic of *Becker Muscular Dystrophy*, which is a milder form. * **Option D:** Cardiac muscle is **not normal**. Dilated cardiomyopathy and arrhythmias are common as the disease progresses, and respiratory or cardiac failure is the leading cause of death. **High-Yield Clinical Pearls for NEET-PG:** * **Gower’s Sign:** Use of hands to "climb up" the legs to stand, indicating proximal muscle weakness. * **Pseudohypertrophy:** The calves appear large but are actually composed of fat and connective tissue (fibrosis). * **Diagnosis:** Gold standard is **Genetic Testing** (multiplex PCR for deletions); Muscle biopsy shows absent dystrophin staining. * **Treatment:** Glucocorticoids (e.g., Prednisolone) are the mainstay to improve strength and delay progression. *Note: No citations from the provided reference list were applied as they did not meet the relevance criteria for Duchenne Muscular Dystrophy.*

Question 13: Which of the following statements about hemochromatosis is false?

A. Caused by HFE gene mutation
B. Inherited in an autosomal recessive pattern
C. Leads to iron deposits in the testis (Correct Answer)
D. Secondary hemochromatosis can result from thalassemias

Explanation: The correct answer is **C**. While Hereditary Hemochromatosis (HH) is a multi-system disorder of iron overload, the endocrine dysfunction involving the gonads is **not** primarily due to direct iron deposition in the testes [1]. Instead, it is caused by iron deposition in the **anterior pituitary gland**, leading to selective gonadotropin deficiency (Hypogonadotropic Hypogonadism) [1]. This results in secondary testicular atrophy, decreased libido, and impotence. **Analysis of other options:** * **Option A:** True. Most cases (approx. 85-90%) of classic HH are caused by a mutation in the **HFE gene** (most commonly the C282Y mutation) on Chromosome 6 [1]. * **Option B:** True. HH is inherited in an **autosomal recessive** pattern with variable penetrance [1]. * **Option D:** True. **Secondary hemochromatosis** occurs due to ineffective erythropoiesis (as seen in **Thalassemias** or Sideroblastic anemia) and chronic blood transfusions, leading to systemic iron overload despite a normal HFE gene. **NEET-PG High-Yield Pearls:** * **Classic Triad (Bronze Diabetes):** Cirrhosis, Diabetes Mellitus, and Skin Hyperpigmentation (occurs in late stages) [1]. * **Most Common Joint Involved:** Second and third metacarpophalangeal (MCP) joints (hook-like osteophytes). * **Cardiac Involvement:** Typically presents as Restrictive Cardiomyopathy (early) or Dilated Cardiomyopathy (late). * **Diagnosis:** Best initial screening test is **Transferrin Saturation** (>45%); Gold standard for HFE-HH is **Genetic Testing** [2]. * **Treatment:** Therapeutic phlebotomy is the mainstay of management [2].

Question 14: Males who are sexually underdeveloped with rudimentary testes and prostate glands, sparse pubic and facial hair, long arms and legs and large hands and feet are likely to have which chromosome complement?

A. 45, XYY
B. 46, XY
C. 47, XXY (Correct Answer)
D. 45, X0

Explanation: The clinical presentation described—hypogonadism (rudimentary testes/prostate), lack of secondary sexual characteristics (sparse hair), and **eunuchoid body habitus** (long extremities)—is the classic triad of **Klinefelter Syndrome** [1]. **1. Why 47, XXY is correct:** Klinefelter Syndrome is the most common cause of congenital hypogonadism in males [2]. The presence of an extra X chromosome leads to testicular dysgenesis [2]. Specifically, the destruction of seminiferous tubules results in low testosterone and elevated gonadotropins (Hypergonadotropic Hypogonadism) [1]. The increased height and long limbs are attributed to the overexpression of the **SHOX gene** (located on the X chromosome), which remains active and delays epiphyseal closure. **2. Analysis of Incorrect Options:** * **45, XYY (Jacob’s Syndrome):** These individuals are usually phenotypically normal, very tall, and may have cystic acne or behavioral issues, but they do not have underdeveloped genitalia or sparse hair. * **46, XY:** This is the normal male karyotype. * **45, X0 (Turner Syndrome):** This presents in females with short stature, webbed neck, and streak ovaries [3]. It is the polar opposite of the tall, male phenotype described. **3. High-Yield Clinical Pearls for NEET-PG:** * **Lab Findings:** ↓ Testosterone, ↑ LH, ↑ FSH, and ↑ Estradiol (leading to **Gynecomastia**) [1]. * **Histology:** Fibrosis and hyalinization of seminiferous tubules with **Leydig cell hyperplasia** [1]. * **Key Risk:** These patients have a significantly higher risk of **Breast Cancer** (20x) and **Extragonadal Germ Cell Tumors** [4]. * **Mental Health:** Often associated with mild intellectual disability or executive dysfunction [1].

Question 15: A family consists of a husband, wife, and children. The wife's father has Huntington's chorea. Which statement is true regarding this genetic condition?

A. The chance of a child inheriting the disease is 1:4.
B. The disease can manifest up to the age of 50.
C. If the wife does not develop the disease by age 50, her children will not be affected. (Correct Answer)
D. Huntington's chorea is caused by a point mutation in a gene.

Explanation: **Explanation:** **Huntington’s Chorea** is an **Autosomal Dominant (AD)** neurodegenerative disorder characterized by choreiform movements, psychiatric disturbances, and progressive dementia. **1. Why Option C is Correct:** Huntington’s disease is a condition of **complete penetrance**. In an AD pedigree, if an individual does not inherit the mutated gene, they cannot pass it on to their offspring (skipping a generation does not occur). Since the typical age of onset is 30–50 years, if the wife reaches age 50 without developing symptoms, it is clinically inferred that she did not inherit the gene from her father. Consequently, her children are at no risk of inheriting the disease. **2. Analysis of Incorrect Options:** * **Option A:** Since it is an Autosomal Dominant trait, the risk for each child of an affected parent is **50% (1:2)**, not 25% (1:4). * **Option B:** While the peak onset is 30–50 years, the disease can manifest at **any age**, including juvenile forms (associated with paternal transmission) or late-onset forms after age 60. * **Option D:** Huntington’s is caused by a **Trinucleotide Repeat Expansion (CAG)** on Chromosome 4, not a simple point mutation. **High-Yield Clinical Pearls for NEET-PG:** * **Genetic Basis:** CAG repeats in the *Huntingtin* gene. Normal is <26 repeats; >40 repeats is diagnostic. * **Anticipation:** The disease shows "anticipation" (earlier onset/increased severity in successive generations), specifically during **paternal transmission** due to instability during spermatogenesis. * **Neuroimaging:** Classic finding is **atrophy of the Caudate Nucleus**, leading to "boxcar ventricles" (enlargement of the frontal horns of lateral ventricles). * **Neurochemistry:** Characterized by decreased levels of **GABA and Acetylcholine**, and increased **Dopamine**.

Question 16: What is the incidence of Down's syndrome directly proportional to?

A. Parity
B. Consanguinity
C. Maternal age (Correct Answer)
D. Mutations

Explanation: The correct answer is **Maternal Age**. Down’s syndrome (Trisomy 21) is primarily caused by **meiotic non-disjunction**, where chromosomes fail to separate properly during oogenesis. As a woman ages, the primary oocytes (which have been arrested in Prophase I since birth) undergo "biological aging." This leads to a breakdown in the spindle apparatus and cohesive proteins, significantly increasing the risk of chromosomal errors. While the risk is approximately 1 in 1,500 at age 20, it rises sharply to 1 in 100 by age 40 and 1 in 25 by age 45. **Analysis of Incorrect Options:** * **Parity:** The number of previous pregnancies does not influence chromosomal non-disjunction; a first-time mother at age 40 has the same risk as a multiparous woman of the same age. * **Consanguinity:** This increases the risk of **autosomal recessive** disorders (e.g., Thalassemia, Wilson’s disease) by bringing together rare recessive alleles, but it does not cause numerical chromosomal aberrations like Trisomy 21. * **Mutations:** While Down’s syndrome is a genetic abnormality, it is typically a **cytogenetic error** (aneuploidy) rather than a point mutation or a specific gene defect. **High-Yield Clinical Pearls for NEET-PG:** * **Most common cause:** Meiotic non-disjunction (95% of cases), most often occurring during Maternal Meiosis I. * **Robertsonian Translocation:** Accounts for ~4% of cases; unlike non-disjunction, this type is **not** related to maternal age and carries a high recurrence risk if a parent is a carrier. * **Screening:** The "Quadruple Screen" (done at 15-20 weeks) typically shows **Low AFP, Low uE3, High hCG, and High Inhibin-A.** * **Ultrasound marker:** Increased Nuchal Translucency (NT) in the first trimester.

Question 17: Turner's syndrome is characterized by which of the following findings, except?

A. Renal malformations
B. Primary amenorrhea
C. Lymphedema
D. Tall stature (Correct Answer)

Explanation: **Explanation:** Turner’s syndrome (45,XO) is the most common sex chromosome abnormality in females [1], [5]. The hallmark of this condition is **short stature**, not tall stature [1]. This is primarily due to the haploinsufficiency of the **SHOX gene** (Short Stature Homeobox gene) located on the distal part of the X chromosome. **Why "Tall Stature" is the correct answer (the exception):** Patients with Turner’s syndrome typically have a height below the 3rd percentile. Growth failure is often the most consistent clinical feature. In contrast, tall stature is associated with conditions like Marfan syndrome, Klinefelter syndrome (47,XXY), or XYY syndrome [2]. **Analysis of incorrect options:** * **Renal malformations:** Approximately 30-50% of patients have renal anomalies, the most classic being the **Horseshoe kidney**. Other findings include duplication of the collecting system. * **Primary amenorrhea:** This occurs due to **gonadal dysgenesis** (streak ovaries) [4]. The accelerated loss of oocytes leads to premature ovarian failure, resulting in hypergonadotropic hypogonadism [3]. * **Lymphedema:** Congenital lymphedema of the hands and feet is a common neonatal presentation [5]. It is caused by lymphatic hypoplasia and often results in a "webbed neck" (cystic hygroma) later in life. **High-Yield Clinical Pearls for NEET-PG:** * **Cardiac:** Bicuspid aortic valve (most common) and Coarctation of the aorta. * **Dermatological:** Multiple pigmented nevi and high-arched palate. * **Endocrine:** Increased risk of Hashimoto’s thyroiditis and Celiac disease. * **Karyotype:** 45,XO is the most common, but mosaicism (45,X/46,XX) can present with milder features and secondary amenorrhea [5].

Question 18: What is the cause of thick pancreatic secretions in cystic fibrosis?

A. Overproduction of mucin
B. Failure to clear mucin due to epithelial dysfunction
C. Defect in chloride channel leading to water reabsorption (Correct Answer)
D. Defect in sodium channel leading to water reabsorption

Explanation: **Explanation:** The fundamental defect in Cystic Fibrosis (CF) is a mutation in the **CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene**, which encodes a cAMP-regulated chloride channel. **Why Option C is Correct:** In the pancreas and respiratory tract, the CFTR protein normally pumps chloride ions *out* of the epithelial cells into the lumen. This creates an osmotic gradient that draws water into the secretions, keeping them hydrated and fluid. In CF, the defective channel prevents chloride secretion. Consequently, there is a compensatory **increase in sodium and water reabsorption** from the lumen into the cells to maintain isotonicity. This dehydration of the luminal surface leads to the formation of viscid, inspissated (thick) secretions that obstruct pancreatic ducts, leading to exocrine insufficiency and fibrosis. **Why Other Options are Incorrect:** * **Option A & B:** While mucin clearance is impaired, the primary pathology is not an overproduction of mucin or a simple mechanical failure of the epithelium; it is the secondary result of the underlying electrolyte and water imbalance. * **Option D:** The primary defect is in the **chloride channel**, not the sodium channel (ENaC). While sodium reabsorption is increased, it is a secondary physiological response to the chloride transport failure. **High-Yield Clinical Pearls for NEET-PG:** * **Genetics:** Most common mutation is **ΔF508** (Class II defect: protein misfolding and trafficking failure). * **Sweat Gland Paradox:** Unlike the pancreas, in sweat glands, CFTR normally *reabsorbs* chloride. Therefore, CF patients have **high sweat chloride** (>60 mEq/L), which is the gold standard for diagnosis. * **Meconium Ileus:** The earliest clinical manifestation of CF in neonates. * **Infertility:** 95% of males are infertile due to **Congenital Bilateral Absence of Vas Deferens (CBAVD)**.

Question 19: What is the most common mutated gene in primary hemochromatosis?

A. HFE gene (Correct Answer)
B. Transferrin receptor 2
C. Ferroportin 1
D. Hepcidin

Explanation: **Primary (Hereditary) Hemochromatosis** is an autosomal recessive disorder characterized by excessive intestinal iron absorption leading to systemic iron overload [2]. **Why HFE is the Correct Answer:** The **HFE gene** (located on Chromosome 6) is the most common cause of primary hemochromatosis, accounting for over 80-90% of cases in clinical practice [2]. The most frequent mutation is the **C282Y** substitution (cysteine to tyrosine), followed by the H63D mutation [1]. The HFE protein normally regulates the interaction between the transferrin receptor and hepcidin; its mutation leads to inappropriately low hepcidin levels, causing uncontrolled iron entry into the plasma. **Why Other Options are Incorrect:** * **Transferrin receptor 2 (TfR2):** Mutations here cause Type 3 Hereditary Hemochromatosis. It is much rarer than HFE-related disease. * **Ferroportin 1 (SLC40A1):** Mutations lead to Type 4 Hemochromatosis (Ferroportin disease). Unlike other types, this often presents with high ferritin but low-to-normal transferrin saturation initially. * **Hepcidin (HAMP):** Mutations in the HAMP gene cause Type 2B Juvenile Hemochromatosis, a rare and severe form that presents in the second decade of life with early cardiac and endocrine failure. **High-Yield Clinical Pearls for NEET-PG:** * **Classic Triad (Bronze Diabetes):** Cirrhosis, Diabetes Mellitus, and Skin Hyperpigmentation (occurs late) [2]. * **Screening Test of Choice:** Transferrin Saturation (>45% is highly suggestive). * **Confirmatory Test:** HFE Gene Analysis (Genetic testing) [1]. * **MRI Findings:** "Signal dropout" on T2-weighted images due to iron deposition in the liver [1]. * **Treatment:** Therapeutic Phlebotomy is the mainstay of management [1]. * **Arthropathy:** Characteristically involves the 2nd and 3rd metacarpophalangeal (MCP) joints with "hook-like" osteophytes.

Question 20: Down's syndrome is characterized by which chromosomal abnormality?

A. Triploidy
B. Monosomy
C. Trisomy (Correct Answer)
D. Aneuploidy

Explanation: **Explanation:** **Down Syndrome (Trisomy 21)** is the most common chromosomal disorder and a frequent topic in NEET-PG. The correct answer is **Trisomy** because the condition is characterized by the presence of an extra copy of chromosome 21 (47, XX/XY, +21). This occurs primarily due to **meiotic non-disjunction** (95% of cases), most commonly during maternal meiosis I. **Analysis of Options:** * **Triploidy (A):** This refers to a complete extra set of chromosomes (3n = 69). It is usually incompatible with life and results in early spontaneous abortion. * **Monosomy (B):** This is the absence of one member of a pair of chromosomes (e.g., Turner Syndrome, 45, XO). Autosomal monosomies are lethal. * **Aneuploidy (D):** While Down Syndrome *is* a type of aneuploidy (an abnormal number of chromosomes), **Trisomy** is the more specific and clinically accurate description. In competitive exams, always choose the most specific term provided. **High-Yield Clinical Pearls for NEET-PG:** * **Risk Factor:** Advanced maternal age (>35 years) is the strongest risk factor for non-disjunction. * **Genetics:** 95% are due to Trisomy 21, 3-4% due to **Robertsonian Translocation** (usually t(14;21)), and 1-2% due to **Mosaicism**. * **Screening:** First-trimester screening shows **increased Nuchal Translucency**, decreased PAPP-A, and increased β-hCG. * **Associations:** Endocardial cushion defects (AVSD), Duodenal atresia ("Double bubble" sign), Early-onset Alzheimer’s, and increased risk of ALL/AML (M7 subtype).

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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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