Genetics and Disease — MCQs

Genetics and Disease Indian Medical PG Practice Questions and MCQs

Question 121: Which one of the following neurological conditions is not inherited in an autosomal dominant pattern?

A. Neurofibromatosis
B. Friedreich's ataxia (Correct Answer)
C. Marfan's syndrome
D. Bloom syndrome

Explanation: **Explanation:** The core concept tested here is the mode of inheritance for common genetic syndromes encountered in neurology and medicine. **1. Why Friedreich’s Ataxia is the correct answer:** Friedreich’s ataxia (FA) is an **Autosomal Recessive (AR)** condition. It is the most common inherited ataxia and 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 damage, primarily affecting the spinocerebellar tracts, dorsal columns, and pyramidal tracts [1]. **2. Analysis of Incorrect Options:** * **Neurofibromatosis (Type 1 and 2):** Both are classic examples of **Autosomal Dominant (AD)** inheritance. NF1 is linked to Chromosome 17, and NF2 to Chromosome 22. * **Marfan’s Syndrome:** This is an **AD** connective tissue disorder caused by mutations in the *FBN1* gene (encoding Fibrillin-1) on Chromosome 15. * **Bloom Syndrome:** While the question asks for "neurological conditions," Bloom syndrome is primarily a chromosomal instability disorder. However, it is **Autosomal Recessive**, making it technically a correct answer alongside Friedreich's ataxia. *Note: In standard NEET-PG patterns, if two options are AR, Friedreich's ataxia is the "more" neurological choice.* **3. High-Yield Clinical Pearls for NEET-PG:** * **Friedreich’s Ataxia Triad:** Progressive ataxia, HOCM (Hypertrophic Obstructive Cardiomyopathy), and Diabetes Mellitus. Skeletal deformities like **Pes Cavus** and Kyphoscoliosis are common. * **Trinucleotide Repeat Mnemonic:** "GAA" for Friedreich’s Ataxia (**G**ait **A**taxia **A**lways). * **Most AD conditions** involve structural protein defects (e.g., Marfan, NF, Achondroplasia). * **Most AR conditions** involve enzyme deficiencies or metabolic pathways [2] (e.g., Wilson’s disease, Hemochromatosis, FA).

Question 122: Mitochondrial chromosomal abnormalities lead to which of the following conditions?

A. Leber's hereditary optic neuropathy (Correct Answer)
B. Angelman syndrome
C. Prader-Willi syndrome
D. Myotonic dystrophy

Explanation: ### Explanation **Mitochondrial inheritance** is a non-Mendelian pattern where mutations occur in the extranuclear mitochondrial DNA (mtDNA) [2]. Since mitochondria are inherited exclusively from the oocyte, these diseases are transmitted only by females to all their offspring, while affected males never pass the condition to their children. #### Why the Correct Answer is Right: **A. Leber's Hereditary Optic Neuropathy (LHON):** This is the classic example of a mitochondrial DNA mutation (typically involving genes for NADH dehydrogenase). It presents as painless, subacute bilateral central vision loss, primarily in young adult males [1]. Other examples of mitochondrial diseases include MELAS, MERRF, and Kearns-Sayre syndrome [1]. #### Why the Other Options are Wrong: * **B & C. Angelman and Prader-Willi Syndromes:** These are examples of **Genomic Imprinting** involving chromosome 15. Prader-Willi results from the loss of the paternal allele, while Angelman results from the loss of the maternal allele (specifically the UBE3A gene). * **D. Myotonic Dystrophy:** This is an **Autosomal Dominant** condition characterized by **Trinucleotide Repeat Expansion** (CTG repeat in the DMPK gene). It exhibits "Anticipation," where the disease becomes more severe in successive generations. #### NEET-PG High-Yield Pearls: * **Heteroplasmy:** A key concept in mitochondrial genetics where a cell contains a mixture of both normal and mutated mtDNA. The severity of the disease depends on the proportion of mutated mitochondria. * **Tissues Affected:** Mitochondrial diseases primarily affect high-energy-demand tissues: the CNS (seizures, stroke-like episodes), Skeletal Muscle (weakness, "Ragged Red Fibers" on Gomori trichrome stain), and the Heart [1]. * **Maternal Inheritance:** If a question mentions a mother passing a trait to all children but the father passing it to none, always think Mitochondrial Inheritance.

Question 123: Which of the following is an autosomal dominant disorder?

A. Tuberous sclerosis
B. Von Hippel-Lindau disease
C. Neurofibromatosis
D. All of the above (Correct Answer)

Explanation: **Explanation:** The correct answer is **D. All of the above**. All three conditions listed belong to a group of disorders known as **Phakomatoses** (neurocutaneous syndromes), which are classically inherited in an **Autosomal Dominant (AD)** pattern. 1. **Tuberous Sclerosis (TSC):** Caused by mutations in the *TSC1* (Hamartin) or *TSC2* (Tuberin) genes. It is characterized by the triad of seizures, mental retardation, and adenoma sebaceum (Vogt’s triad). 2. **Von Hippel-Lindau (VHL) Disease:** Caused by a mutation in the *VHL* gene on chromosome 3p. It predisposes individuals to hemangioblastomas (CNS and retinal), Renal Cell Carcinoma (clear cell type), and Pheochromocytoma. 3. **Neurofibromatosis (NF):** Both NF1 (von Recklinghausen’s disease, chromosome 17) and NF2 (MISME syndrome, chromosome 22) follow an AD inheritance. NF1 is known for Lisch nodules and Café-au-lait spots, while NF2 is characterized by bilateral vestibular schwannomas [1]. **Why the other options are "incorrect" as standalone answers:** While A, B, and C are all autosomal dominant, selecting any single one would be incomplete, as all three share the same inheritance pattern. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for AD disorders:** "Very Powerful DOMINANT Father" (**V**HL, **P**olycystic Kidney Disease, **D**ystrophia Myotonica, **O**steogenesis Imperfecta, **M**arfan’s, **I**ntermittent Porphyria, **N**eurofibromatosis, **A**chondroplasia, **N**oonan Syndrome, **T**uberous Sclerosis, **F**amilial Hypercholesterolemia). * **NF1 Gene:** Chromosome **17** (17 letters in Neurofibromatosis). * **NF2 Gene:** Chromosome **22** (22 for "2" vestibular schwannomas) [1]. * **VHL Gene:** Chromosome **3** (VHL has 3 letters).

Question 124: What is Patau syndrome?

A. Trisomy 13 (Correct Answer)
B. Trisomy 18
C. Trisomy 21
D. Trisomy 22

Explanation: **Explanation:** **Patau syndrome** is a severe chromosomal abnormality caused by **Trisomy 13** (the presence of an extra copy of chromosome 13). It is the least common and most severe of the three viable autosomal trisomies. The condition results from meiotic non-disjunction, most frequently associated with advanced maternal age. **Analysis of Options:** * **A. Trisomy 13 (Correct):** This is the cytogenetic hallmark of Patau syndrome. It leads to defective prechordal mesoderm development, resulting in midline defects. * **B. Trisomy 18:** This is **Edwards syndrome**. It is characterized by "rocker-bottom" feet, clenched fists with overlapping fingers, and micrognathia. * **C. Trisomy 21:** This is **Down syndrome**, the most common viable autosomal trisomy, characterized by intellectual disability, flat facial profile, and Simian crease. * **D. Trisomy 22:** This is a common cause of first-trimester spontaneous abortions but is rarely seen in live births (non-viable) [1]. **High-Yield Clinical Pearls for NEET-PG:** To differentiate the trisomies quickly, remember the **"3 P's"** of Patau Syndrome: 1. **P**olydactyly (Post-axial) 2. **P**alates (Cleft lip and palate) 3. **P**unch-out scalp lesions (**Aplasia cutis congenita**) Other classic findings include **Holoprosencephaly** (failure of the forebrain to divide), microphthalmia, and cystic renal disease. The prognosis is poor, with most infants not surviving beyond the first year of life. Screening typically shows decreased free β-hCG and PAPP-A in the first trimester.

Question 125: A couple has two children affected with tuberous sclerosis. On detailed clinical and laboratory evaluation (including molecular studies), both parents are normal. Which one of the following explains the two affected children in this family?

A. Non-penetrance
B. Uniparental disomy
C. Genomic imprinting
D. Germline mosaicism (Correct Answer)

Explanation: The scenario describes a classic case of **Germline Mosaicism**. Tuberous Sclerosis (TSC) is an autosomal dominant disorder. When two phenotypically and genetically normal parents (confirmed by molecular studies) have multiple children with the same autosomal dominant condition, germline mosaicism is the most likely explanation. **1. Why Germline Mosaicism is correct:** Germline (or gonadal) mosaicism occurs when a mutation happens in a precursor germ cell during the parent's development [1]. Consequently, a subset of the parent's gametes (sperm or eggs) carries the mutation, while their somatic cells do not. This allows the parent to remain clinically normal and test negative on blood-based molecular studies, yet pass the mutation to multiple offspring. **2. Why other options are incorrect:** * **Non-penetrance:** This refers to an individual who carries the disease genotype but shows no clinical symptoms. However, molecular studies would still detect the mutation in the parent's DNA, which is not the case here. * **Uniparental Disomy (UPD):** This occurs when a child inherits two copies of a chromosome from one parent and none from the other. While it can cause disease (e.g., Prader-Willi), it does not typically explain the recurrence of an autosomal dominant trait from normal parents. * **Genomic Imprinting:** This involves differential gene expression depending on the parent of origin. It explains why a disease manifests differently based on which parent passed the gene, but it does not explain how "normal" parents produce multiple affected children. **Clinical Pearls for NEET-PG:** * **Tuberous Sclerosis Complex (TSC):** Caused by mutations in *TSC1* (Hamartin) or *TSC2* (Tuberin). * **Vogt’s Triad:** Adenoma sebaceum (facial angiofibromas), mental retardation, and seizures. * **Ash-leaf spots:** Often the earliest sign (Wood’s lamp examination). * **Suspect Germline Mosaicism** in exams whenever "normal parents" have "multiple affected children" with an autosomal dominant condition (also common in Osteogenesis Imperfecta and Duchenne Muscular Dystrophy).

Question 126: The gene for myotonic dystrophy is coded on which chromosome number?

A. 19 (Correct Answer)
B. 20
C. 21
D. 24

Explanation: **Explanation:** The correct answer is **Option A (Chromosome 19)**. Myotonic Dystrophy Type 1 (DM1), also known as Steinert’s disease, is the most common form of adult-onset muscular dystrophy. It is an **autosomal dominant** multisystem disorder caused by an unstable **CTG trinucleotide repeat** expansion in the **DMPK gene** (Dystrophia Myotonica Protein Kinase), which is located on the long arm of **chromosome 19 (19q13.3)**. **Analysis of Options:** * **Option A (19):** Correct. This chromosome houses the DMPK gene. The severity of the disease increases with the number of CTG repeats (Genetic Anticipation). * **Option B (20):** Incorrect. Chromosome 20 is associated with conditions like Alagille syndrome or Creutzfeldt-Jakob disease (PRNP gene), but not myotonic dystrophy. * **Option C (21):** Incorrect. Chromosome 21 is famously associated with Down Syndrome (Trisomy 21) and the APP gene linked to early-onset Alzheimer’s. * **Option D (24):** Incorrect. Humans only have 23 pairs of chromosomes (46 total). There is no "Chromosome 24" in the human genome. **High-Yield Clinical Pearls for NEET-PG:** * **Trinucleotide Repeat:** CTG (Mnemonic: **C**ataract, **T**oupee/Baldness, **G**onadal atrophy). * **Clinical Features:** "Hatchet facies" (wasting of temporalis/masseter), frontal balding, cataracts, cardiomyopathy (conduction blocks), and myotonia (delayed muscle relaxation, e.g., difficulty releasing a handshake). * **Myotonic Dystrophy Type 2 (DM2):** Caused by a **CCTG** tetranucleotide repeat on **Chromosome 3** (ZNF9 gene). * **Anticipation:** Symptoms become more severe and appear at an earlier age in successive generations, typically seen when inherited from the mother in DM1.

Question 127: Which of the following statements is FALSE regarding Marfan's syndrome?

A. Autosomal dominant inheritance
B. Mutation in the fibrillin 1 gene
C. Inferonasal subluxation of the lens (Correct Answer)
D. All of the above

Explanation: **Explanation:** Marfan’s syndrome is a multi-system connective tissue disorder. The question asks for the **FALSE** statement regarding its clinical and genetic profile. **1. Why Option C is the Correct (False) Statement:** In Marfan’s syndrome, the classic ocular finding is **Ectopia Lentis** (subluxation of the lens). Crucially, the displacement is typically **Superotemporal** (upward and outward). * **Inferonasal** (downward and inward) subluxation is characteristic of **Homocystinuria**, not Marfan’s. This is a high-yield distinction for NEET-PG. **2. Why the other options are true:** * **Option A (Autosomal Dominant):** Marfan’s syndrome follows an autosomal dominant inheritance pattern with high penetrance but variable expressivity [1]. * **Option B (Fibrillin 1 gene):** The condition is caused by a mutation in the **FBN1 gene** located on **chromosome 15q21**, which encodes the glycoprotein fibrillin-1. This protein is essential for the structural integrity of microfibrils in the extracellular matrix. **Clinical Pearls for NEET-PG:** * **Cardiovascular:** The most common cause of death is **Aortic Root Dilatation** leading to aortic dissection or regurgitation [1]. Mitral Valve Prolapse (MVP) is also common. * **Skeletal:** Patients exhibit dolichostenomelia (long limbs), arachnodactyly (long fingers), and positive **Walker-Murdoch** (wrist) and **Steinberg** (thumb) signs. * **Diagnostic Criteria:** Diagnosis is based on the **Ghent Nosology**, which emphasizes aortic root aneurysm and ectopia lentis. * **Management:** Beta-blockers or Losartan (ARBs) are used to slow the rate of aortic dilatation.

Question 128: Which chromosome is associated with Alzheimer's disease?

A. Chromosome 2
B. Chromosome 6
C. Chromosome 12
D. Chromosome 19 (Correct Answer)

Explanation: Alzheimer’s Disease (AD) is genetically heterogeneous, involving both early-onset (familial) and late-onset (sporadic) forms [1]. The correct answer is **Chromosome 19** because it houses the **APOE (Apolipoprotein E) gene**. The **APOE-ε4 allele** is the most significant genetic risk factor for late-onset AD, which accounts for >95% of cases. Inheriting one ε4 allele increases risk 3-fold, while two alleles increase risk 12-fold. **Analysis of Options:** * **Chromosome 19 (Correct):** Site of the APOE gene. It is associated with the sporadic, late-onset form of the disease. * **Chromosome 2:** Not traditionally associated with AD. It is linked to conditions like LPIN1 deficiency or certain types of colon cancer (MSH2/6). * **Chromosome 6:** Contains the Major Histocompatibility Complex (MHC). While inflammation plays a role in AD, it is not the primary diagnostic chromosome for the disease. * **Chromosome 12:** Some studies suggest a link to the A2M (Alpha-2-macroglobulin) gene, but it is not a classic high-yield association for NEET-PG compared to Chromosomes 21, 14, 1, and 19. **High-Yield Clinical Pearls for NEET-PG:** 1. **Early-Onset AD (Familial):** * **Chromosome 21:** APP (Amyloid Precursor Protein) gene. (Explains why Down Syndrome patients develop AD early). * **Chromosome 14:** Presenilin 1 (PSEN1) – Most common cause of early-onset AD. * **Chromosome 1:** Presenilin 2 (PSEN2). 2. **Protective Factor:** The **APOE-ε2** allele is considered protective against Alzheimer's. 3. **Pathology:** Look for extracellular **Amyloid-beta plaques** and intracellular **Tau protein neurofibrillary tangles** [1].

Question 129: A patient has been diagnosed with Marfan syndrome. Which of the following is the most common cause of death in these patients?

A. Liver disease
B. Myocardial infarction
C. Recurrent infection
D. Aortic disease (Correct Answer)

Explanation: **Explanation:** **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]. This protein is essential for the structural integrity of the extracellular matrix and the regulation of Transforming Growth Factor-beta (TGF-β). **1. Why Aortic Disease is Correct:** The most life-threatening complications of Marfan syndrome involve the cardiovascular system. Defective fibrillin-1 leads to **cystic medial necrosis** of the aorta [1]. This results in progressive **aortic root dilatation**, which can culminate in **aortic dissection** or **aortic rupture** [1]. Historically, these aortic events are the leading cause of mortality in untreated patients. **2. Why Incorrect Options are Wrong:** * **Liver disease (A):** Marfan syndrome does not typically involve the hepatic system; there is no association with cirrhosis or liver failure. * **Myocardial infarction (B):** While Marfan patients may have cardiac issues (like Mitral Valve Prolapse), the primary pathology is in the vessel wall (aorta) rather than atherosclerotic coronary artery disease. * **Recurrent infection (C):** This is characteristic of primary immunodeficiency syndromes (e.g., SCID or CVID), not structural connective tissue disorders. **3. High-Yield Clinical Pearls for NEET-PG:** * **Most common cause of death:** Aortic dissection/rupture [1]. * **Most common cardiac abnormality:** Mitral Valve Prolapse (MVP). * **Skeletal features:** Arachnodactyly, pectus excavatum, and a high arm span-to-height ratio (>1.05). * **Ocular hallmark:** Ectopia lentis (typically **upward** and outward subluxation). * **Management:** Beta-blockers or ARBs (Losartan) are used to slow the rate of aortic dilatation. Prophylactic surgery is indicated when the aortic diameter exceeds 5 cm.

Question 130: What is the earliest muscle to be involved in dermatomyositis?

A. Deltoid
B. Gluteal
C. Lumbricals
D. Quadriceps (Correct Answer)

Explanation: **Explanation:** Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterized by symmetric, **proximal muscle weakness** [1]. While the disease typically affects the limb-girdle muscles, the **Quadriceps** (thigh muscles) are clinically recognized as the earliest muscles to be involved and often the most severely affected. Patients typically present with difficulty rising from a seated position or climbing stairs before upper limb involvement becomes prominent [1]. **Analysis of Options:** * **Quadriceps (Correct):** These are the primary proximal muscles of the lower limb. In the progression of DM, lower extremity proximal weakness usually precedes or is more symptomatic than upper extremity weakness at the onset [1]. * **Deltoid (Incorrect):** While the deltoid is a proximal muscle and is frequently involved in DM, it typically follows the involvement of the pelvic girdle/thigh muscles. * **Gluteal (Incorrect):** These are proximal muscles involved in the disease process, but clinical studies and electromyography (EMG) findings point to the quadriceps as the earliest site of functional deficit. * **Lumbricals (Incorrect):** Dermatomyositis characteristically **spares distal muscles** (like the lumbricals of the hand) until very late stages of the disease. **Clinical Pearls for NEET-PG:** * **Pathognomonic Signs:** Gottron’s papules (over MCP/PIP joints) and Heliotrope rash (periorbital edema with violaceous hue) [2]. * **Muscle Biopsy:** Shows **perifascicular atrophy** (pathognomonic) and perivascular inflammation. * **Malignancy:** DM has a strong association with internal malignancies (e.g., ovarian, lung, gastric) [2]. Age-appropriate cancer screening is mandatory. * **Antibody:** **Anti-Mi-2** is highly specific for dermatomyositis and carries a good prognosis.

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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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