Genetics and Disease Practice Questions

Q: Which one of the following is an autosomal dominant type of genetic disorder?

Tuberous sclerosis. **Explanation:** **Tuberous Sclerosis (Option D)** is the correct answer. It is an **autosomal dominant (AD)** neurocutaneous syndrome caused by mutations in the *TSC1* (Hamartin) or *TSC2* (Tuberin) genes. In AD disorders, a single copy of the mutant gene is sufficient to cause the disease, typically manifesting in every generation. **Analysis of Incorrect Options:** * **Color Blindness (Option A) and Hemophilia (Option B):** These are classic examples of **X-linked recessive (XLR)** disorders. They primarily affect males, while females are typically asymptomatic carriers. * **Phenylketonuria (Option C):** This is an **autosomal recessive (AR)** metabolic disorder. It requires two copies of the defective gene (one from each parent) for the disease to manifest. Most enzyme deficiencies, like PKU, follow an AR inheritance pattern. **Clinical Pearls for NEET-PG:** * **Tuberous Sclerosis Triad (Vogt’s Triad):** Adenoma sebaceum (facial angiofibromas), seizures, and mental retardation (seen in only ~30% of cases). * **High-Yield Features:** Ash-leaf spots (hypopigmented macules - earliest sign), Shagreen patches, subependymal nodules (candle-guttering appearance), and Cardiac Rhabdomyomas. * **Mnemonic for AD Disorders:** "Very Powerful DOMINANT" – **V**on Willebrand/VHL, **P**olycystic Kidney (ADPKD), **D**ystrophia Myotonica, **O**steogenesis Imperfecta, **M**arfan, **I**ntermittent Porphyria, **N**eurofibromatosis, **A**chondroplasia, **N**oonan, **T**uberous Sclerosis.

Q: What is the genotype of a male with Down syndrome?

47, XY. **Explanation:** **1. Correct Answer: B (47, XY)** Down syndrome is characterized by **Trisomy 21**, meaning there are three copies of chromosome 21 instead of the usual two. In a male, the normal chromosomal complement is 46, XY. The addition of one extra autosome (chromosome 21) brings the total count to **47**. Therefore, the genotype is written as **47, XY, +21** (often simplified to 47, XY in MCQ options). The most common cause (95% of cases) is meiotic non-disjunction, which is strongly associated with advanced maternal age. **2. Analysis of Incorrect Options:** * **A. 46, XY:** This represents a **genotypically normal male** [2]. While Down syndrome can rarely occur with 46 chromosomes due to Robertsonian Translocation, the phenotype still requires the genetic material of three chromosome 21s; however, 47, XY is the standard representation of the trisomic state. * **C. 45, XY:** This indicates **monosomy** (loss of a chromosome). Autosomal monosomies are generally incompatible with life [3]. * **D. 47, XXY:** This is the genotype for **Klinefelter Syndrome** [1]. While it also has 47 chromosomes, the extra chromosome is a sex chromosome (X), not an autosome. **3. NEET-PG High-Yield Pearls:** * **Most common cause:** Meiotic non-disjunction (95%). * **Translocation type:** Robertsonian translocation [t(14;21)] accounts for ~4% and is independent of maternal age. * **Screening:** First-trimester screening includes **increased Nuchal Translucency (NT)**, decreased PAPP-A, and increased β-hCG. * **Quadruple Test (2nd Trimester):** Low AFP, Low Estriol, High hCG, and **High Inhibin A** (Inhibin is the most sensitive marker here). * **Clinical Associations:** Endocardial cushion defects (ASD/VSD), early-onset Alzheimer’s, and increased risk of ALL (Acute Lymphoblastic Leukemia) and AML (specifically M7 subtype).

Q: A 40-year-old male presented to the ER with generalized tonic-clonic seizure. This was his first episode and he gave a history of intermittent bloody stools for the past 5 months. Investigations included MRI scan of the head, CECT abdomen, and colonoscopy. What is the most common inheritance pattern of the condition suggested by this presentation?

Autosomal dominant. The clinical presentation of a middle-aged male with **generalized tonic-clonic seizures** (suggesting a brain tumor) and **intermittent bloody stools** (suggesting colonic polyposis) is classic for **Turcot Syndrome**. Turcot syndrome is a variant of hereditary polyposis syndromes characterized by the association of **familial adenomatous polyposis (FAP)** or Lynch syndrome with **Central Nervous System (CNS) tumors** (most commonly medulloblastoma or glioblastoma multiforme). 1. **Why Autosomal Dominant is correct:** The majority of hereditary polyposis syndromes, including **FAP (APC gene mutation)** and **Lynch Syndrome (Mismatch repair genes)**, follow an **Autosomal Dominant (AD)** inheritance pattern [1]. Since Turcot syndrome is a phenotypic variant of these conditions, it primarily follows the AD pattern. (Note: A rarer subtype associated with *MUTYH* mutations follows autosomal recessive inheritance [2], but AD remains the classic and most common pattern tested). 2. **Why other options are incorrect:** * **Autosomal Recessive:** While some rare polyposis conditions like MAP (MUTYH-associated polyposis) are recessive [2], they are not the "most common" pattern for the classic Turcot/FAP presentation. * **X-linked Patterns:** There are no major hereditary colorectal cancer syndromes that follow X-linked inheritance. ### Clinical Pearls for NEET-PG: * **Turcot Syndrome Type 1:** Associated with Lynch Syndrome (HNPCC); common CNS tumor is **Glioblastoma Multiforme**. * **Turcot Syndrome Type 2:** Associated with FAP; common CNS tumor is **Medulloblastoma**. * **Gardner Syndrome:** Another AD variant of FAP presenting with colonic polyps + Osteomas (mandible) + Soft tissue tumors (Desmoid tumors) + Sebaceous cysts [2]. * **Rule of Thumb:** Most "Cancer Predisposition Syndromes" involving tumor suppressor genes (APC, BRCA, RB, TP53) are inherited in an **Autosomal Dominant** fashion [1].

Q: Hypokalemic periodic paralysis is inherited as an autosomal dominant disorder with incomplete penetrance. It is caused by a mutation in which of the following channels?

Calcium channel. **Explanation:** **Hypokalemic Periodic Paralysis (HOKPP)** is the most common form of periodic paralysis [1]. It is characterized by episodic muscle weakness triggered by factors that lower serum potassium levels, such as high-carbohydrate meals or strenuous exercise [1]. **Why the Correct Answer is Right:** The primary defect in **Type 1 HOKPP** (accounting for ~70% of cases) is a mutation in the **CACNA1S gene**, which encodes the **α1-subunit of the L-type voltage-gated calcium channel** (Dihydropyridine receptor) in skeletal muscle. This mutation results in an aberrant "gating pore current" that leads to muscle membrane depolarization and inexcitability during periods of low extracellular potassium. **Analysis of Incorrect Options:** * **A. Sodium channel:** Mutations in the **SCN4A** gene (Sodium channel) cause **Hyperkalemic** Periodic Paralysis [1]. While a small subset of HOKPP (Type 2) is caused by sodium channel mutations, the classic and most frequent association taught for exams is the calcium channel. * **B. Potassium channel:** Mutations in potassium channels (e.g., KCNJ2) are associated with **Andersen-Tawil Syndrome**, which presents with periodic paralysis, cardiac arrhythmias (long QT), and skeletal abnormalities. * **C. Chloride channel:** Mutations in the **CLCN1** chloride channel cause **Myotonia Congenita** (Thomsen and Becker diseases), characterized by delayed muscle relaxation rather than episodic paralysis [1]. **Clinical Pearls for NEET-PG:** * **Triggers:** High carb intake (insulin shifts K+ intracellularly), rest after exercise, and stress [1]. * **Treatment:** Acute attacks are treated with oral/IV Potassium. Prophylaxis involves **Acetazolamide** (carbonic anhydrase inhibitor) or potassium-sparing diuretics. * **Thyrotoxic Periodic Paralysis:** A common differential in Asian males; it presents identically to HOKPP but is associated with hyperthyroidism.

Q: Which of the following is NOT a mitochondrial disease?

Spino-cerebellar ataxia. The correct answer is **D. Spino-cerebellar ataxia (SCA)**. **1. Why Spino-cerebellar ataxia is the correct answer:** Mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA) or nuclear DNA encoding mitochondrial proteins, typically following a **maternal inheritance** pattern [1]. **Spino-cerebellar ataxia (SCA)**, however, is a group of neurodegenerative disorders primarily caused by **autosomal dominant** mutations. Most common types (like SCA1, 2, 3, and 7) are characterized by **CAG trinucleotide repeat expansions** in nuclear DNA, not mitochondrial dysfunction. **2. Analysis of Incorrect Options:** * **A. Leber’s Hereditary Optic Neuropathy (LHON):** A classic mitochondrial disease characterized by painless, subacute bilateral vision loss [1]. It is caused by point mutations in mtDNA (e.g., G11778A). * **B. Kearns-Sayre Syndrome (KSS):** A mitochondrial DNA deletion syndrome characterized by the triad of onset before age 20, chronic progressive external ophthalmoplegia (CPEO), and pigmentary retinopathy [1]. * **C. Progressive External Ophthalmoplegia (PEO):** This involves weakness of the extraocular muscles. While it can be part of multisystem syndromes (like KSS), it is fundamentally a manifestation of mitochondrial myopathy [1]. **3. NEET-PG High-Yield Pearls:** * **Maternal Inheritance:** All children of an affected mother inherit the disease, but an affected father never passes it on [1]. * **Heteroplasmy:** The presence of a mixture of wild-type and mutant mtDNA; the "threshold effect" determines clinical severity. * **Ragged Red Fibers:** On Gomori trichrome stain, these are the hallmark of mitochondrial myopathies (accumulation of diseased mitochondria under the sarcolemma). * **Common Mnemonics:** Remember **MELAS** (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes) and **MERRF** (Myoclonic Epilepsy with Ragged Red Fibers).

Q: Which of the following conditions is inherited in an autosomal dominant pattern?

Achondroplasia. **Explanation:** **Achondroplasia (Correct Answer):** Achondroplasia is the most common cause of short-limb dwarfism and is inherited in an **autosomal dominant (AD)** pattern [1]. It is caused by a gain-of-function mutation in the **FGFR3 gene** (Fibroblast Growth Factor Receptor 3) on chromosome 4p. While it is AD, approximately 80% of cases arise from *de novo* mutations, often associated with advanced paternal age. **Incorrect Options:** * **Hemochromatosis (B):** This is an **autosomal recessive (AR)** disorder, most commonly involving the HFE gene (C282Y mutation). It leads to excessive iron absorption and deposition in organs like the liver, heart, and pancreas. * **Wilson's Disease (C):** This is an **AR** disorder of copper metabolism caused by mutations in the ATP7B gene on chromosome 13, leading to copper accumulation in the liver and basal ganglia (Kayser-Fleischer rings). * **Cystic Fibrosis (D):** This is a classic **AR** disorder caused by mutations in the CFTR gene on chromosome 7, affecting chloride transport and leading to thick secretions in the lungs and pancreas. **High-Yield Clinical Pearls for NEET-PG:** * **Rule of Thumb:** Most structural protein defects (e.g., Achondroplasia, Marfan syndrome) are **Autosomal Dominant**, whereas most enzyme deficiencies (e.g., Wilson’s, Hemochromatosis, Glycogen storage diseases) are **Autosomal Recessive**. * **Achondroplasia Key Features:** Rhizomelic (proximal) shortening of limbs, trident hand, frontal bossing, and normal intelligence/life expectancy [1]. * **Advanced Paternal Age:** Strongly linked to *de novo* AD mutations like Achondroplasia and Apert syndrome.

Question 1

Which one of the following is an autosomal dominant type of genetic disorder?

Accepted Answer

Tuberous sclerosis

Answer

Color blindness

Answer

Hemophilia

Answer

Phenylketonuria

Question 2

Which of the following is the primary cause of phenotypic heterogeneity?

Accepted Answer

Allele mutation

Answer

Variable penetrance

Answer

Allelic deletion

Answer

Variable expressivity

Question 3

What is the genotype of a male with Down syndrome?

Accepted Answer

47, XY

Answer

46, XY

Answer

45, XY

Answer

47, XXY

Question 4

A 36-year-old male patient with a family history of dementia is being considered for genetic testing. What type of genetic test is most appropriate in this scenario?

Accepted Answer

Genetic carrier test

Answer

Presymptomatic test

Answer

Post-symptomatic test

Answer

Genetic presymptomatic test

Question 5

A 40-year-old male presented to the ER with generalized tonic-clonic seizure. This was his first episode and he gave a history of intermittent bloody stools for the past 5 months. Investigations included MRI scan of the head, CECT abdomen, and colonoscopy. What is the most common inheritance pattern of the condition suggested by this presentation?

Accepted Answer

Autosomal dominant

Answer

Autosomal recessive

Answer

X-linked recessive

Answer

X-linked dominant

Question 6

What is the most common cause of death in individuals with Klinefelter's syndrome?

Accepted Answer

Infections

Answer

Cardiovascular disease

Answer

Respiratory disease

Answer

Suicide

Question 7

Hypokalemic periodic paralysis is inherited as an autosomal dominant disorder with incomplete penetrance. It is caused by a mutation in which of the following channels?

Accepted Answer

Calcium channel

Answer

Sodium channel

Answer

Potassium channel

Answer

Chloride channel

Question 8

Which of the following is NOT a mitochondrial disease?

Accepted Answer

Spino-cerebellar ataxia

Answer

Leber's hereditary optic neuropathy

Answer

Kearns-Sayre syndrome

Answer

Progressive external ophthalmoplegia

Question 9

Which of the following conditions is inherited in an autosomal dominant pattern?

Accepted Answer

Achondroplasia

Answer

Hemochromatosis

Answer

Wilson's disease

Answer

Cystic fibrosis

Question 10

What is the commonest mode of inheritance among diseases with Mendelian inheritance?

Accepted Answer

Autosomal dominant

Answer

Autosomal recessive

Answer

X-linked recessive

Answer

X-linked dominant

Genetics and Disease — MCQs

Genetics and Disease — MCQs

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