Molecular Pathology Practice Questions

Q: Which of the following mutations is seen in Cowden syndrome?

PTEN mutation. **Explanation:** **Cowden Syndrome** is an autosomal dominant disorder characterized by multiple hamartomas and an increased risk of various malignancies. It is caused by a germline mutation in the **PTEN (Phosphatase and Tensin homolog)** gene located on chromosome 10q23. **PTEN** is a critical tumor suppressor gene that encodes a lipid phosphatase. It acts as a negative regulator of the **PI3K/AKT/mTOR signaling pathway**. When PTEN is mutated or lost, the pathway becomes constitutively active, leading to uncontrolled cell proliferation and survival. Clinically, Cowden syndrome presents with trichilemmomas (skin tumors), oral papillomas, and a high risk of breast, thyroid (follicular), and endometrial carcinomas. **Analysis of Incorrect Options:** * **A. STK 11 mutation:** Associated with **Peutz-Jeghers Syndrome**, characterized by hamartomatous GI polyps and perioral hyperpigmentation. * **B. SMAD 4 mutation:** Associated with **Juvenile Polyposis Syndrome** (along with BMPR1A mutations), which predisposes to gastric and colonic adenocarcinomas. * **D. PTCH mutation:** Associated with **Gorlin Syndrome** (Nevoid Basal Cell Carcinoma Syndrome) [1][2], characterized by multiple basal cell carcinomas, odontogenic keratocysts, and bifid ribs [1][2]. **High-Yield Clinical Pearls for NEET-PG:** * **PTEN** is the most frequently mutated gene in **Endometrial Carcinoma** (Endometrioid type). * Cowden syndrome is part of the **PTEN Hamartoma Tumor Syndrome (PHTS)** spectrum, which also includes Bannayan-Riley-Ruvalcaba syndrome. * **Lhermitte-Duclos disease** (dysplastic gangliocytoma of the cerebellum) is a pathognomonic CNS feature of Cowden syndrome. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Neoplasia, pp. 306-307. [2] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Skin, pp. 1157-1158.

Q: A newly described neurologic disorder affects multiple family members across three generations. In the first generation, two sisters and one brother are affected. In the second generation, all children of the first-generation sisters are affected, but none of the descendants of the first-generation son. In the third generation, all children of the affected second-generation women are affected, but none of the descendants of the second-generation men. What is the most likely mode of inheritance?

Mitochondrial. ### Explanation **Correct Option: C. Mitochondrial Inheritance** The hallmark of **Mitochondrial (Matrilineal) Inheritance** is that the trait is transmitted **only through females** to all of their offspring (both sons and daughters) [1], while affected males never transmit the disorder to their children. In this scenario: 1. **First Generation:** Sisters passed it to all their children; the brother passed it to none. 2. **Second/Third Generation:** Only affected females continued the transmission. This pattern occurs because mitochondria are inherited exclusively from the maternal oocyte; sperm mitochondria are degraded upon fertilization. **Why other options are incorrect:** * **Autosomal Dominant (A):** An affected father would have a 50% chance of passing the trait to his children. Here, the first-generation son had zero affected descendants. [2] * **Autosomal Recessive (B):** This usually skips generations and requires both parents to carry the allele. It does not explain why transmission is strictly tied to the mother’s gender. * **X-linked Dominant (D):** An affected father would pass the trait to **all** of his daughters (as they must receive his X chromosome) but none of his sons. In this case, the father passed it to no one. **High-Yield Clinical Pearls for NEET-PG:** * **Heteroplasmy:** The presence of a mixture of wild-type and mutant mitochondrial DNA within a cell. This explains the **variable expressivity** (severity) seen in mitochondrial diseases. * **High-Energy Tissues:** These disorders primarily affect the CNS, skeletal muscle, and heart (e.g., MELAS, MERRF, Leber’s Hereditary Optic Neuropathy). [1] * **Key Rule:** If a question shows "Affected Mother → All children affected" and "Affected Father → No children affected," always choose Mitochondrial. [1]

Q: Which of the following is NOT an autosomal dominant disorder?

Alkaptonurea. The correct answer is **Alkaptonuria** because it is an **Autosomal Recessive (AR)** disorder, whereas the other options are Autosomal Dominant (AD). **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. Classically, most enzyme deficiencies in metabolic pathways are AR, while structural protein defects are often AD. **2. Analysis of Incorrect Options (AD Disorders):** * **Hereditary Spherocytosis:** A common hemolytic anemia caused by defects in red cell membrane proteins (like spectrin or ankyrin). It is inherited in an **Autosomal Dominant** pattern in 75% of cases. * **Osteogenesis Imperfecta (OI):** Most common types (Type I and Type IV) are **Autosomal Dominant**, resulting from mutations in the COL1A1 or COL1A2 genes affecting Type 1 collagen. * **Gardner Syndrome:** This is a variant of Familial Adenomatous Polyposis (FAP) characterized by colonic polyps, osteomas, and soft tissue tumors. It is inherited in an **Autosomal Dominant** fashion (APC gene mutation). **Clinical Pearls for NEET-PG:** * **Alkaptonuria Triad:** 1. Fresh urine that turns **black** on standing (alkalinization); 2. **Ochronosis** (blue-black pigmentation of cartilage/sclera); 3. Large joint **arthritis**. * **Mnemonic for AD disorders:** "Very Powerful DOMINANT Mother" (**V**on Willebrand, **P**olyposis/PCKD, **D**ystrophia myotonica, **O**steogenesis imperfecta, **M**arfan, **I**ntermittent porphyria, **N**eurofibromatosis, **A**chondroplasia [1], **N**oonan, **T**uberous sclerosis). * **Rule of Thumb:** Most structural/receptor protein defects are AD [1]; most enzyme deficiencies are AR (Exceptions: Hunter syndrome and Fabry disease are X-linked recessive).

Q: The chromosomal karyotype in Patau syndrome is?

47XX,+13. **Explanation:** **Patau Syndrome** is a severe genetic disorder caused by **Trisomy 13**. The correct karyotype is **47,XX,+13** (or 47,XY,+13), indicating an extra copy of chromosome 13. This occurs most commonly due to meiotic non-disjunction during gametogenesis. **Analysis of Options:** * **Option D (Correct):** 47,XX,+13 represents Trisomy 13. It is characterized by the "classic triad" of **Microphthalmia, Cleft lip/palate, and Polydactyly**. * **Option A:** 47,+21 is the karyotype for **Down Syndrome** (Trisomy 21), the most common autosomal trisomy. * **Option B:** 46XX/47,+18 represents **Mosaic Edwards Syndrome**. While +18 is Edwards syndrome, mosaicism occurs when only a percentage of cells carry the extra chromosome. * **Option C:** 45XX,der(14;21) represents a **Robertsonian Translocation**, a common cause of familial Down Syndrome, where the total chromosome count is 45 but genetic material is rearranged. **High-Yield Clinical Pearls for NEET-PG:** * **Patau Syndrome (Trisomy 13):** Look for midline defects (Holoprosencephaly), Scalp defects (Aplasia cutis congenita), and Rocker-bottom feet. * **Edwards Syndrome (Trisomy 18):** Look for Clenched fists (overlapping fingers), Micrognathia, and prominent occiput. * **Mnemonic for Trisomies:** * **P**atau: **P**uberty (Age 13) * **E**dwards: **E**lection (Age 18) * **D**own: **D**rinking (Age 21) * **Prognosis:** Both Trisomy 13 and 18 have a very poor prognosis, with most infants not surviving beyond the first year of life.

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

1 in 1. **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 1

Which of the following mutations is seen in Cowden syndrome?

Accepted Answer

PTEN mutation

Answer

STK 11 mutation

Answer

SMAD 4 mutation

Answer

PTCH mutation

Question 2

A number of structural chromosome abnormalities are seen clinically. No loss of genetic material occurs in which of the following?

Accepted Answer

Inversion

Answer

Deletion

Answer

Insertion

Answer

Substitution

Question 3

A newly described neurologic disorder affects multiple family members across three generations. In the first generation, two sisters and one brother are affected. In the second generation, all children of the first-generation sisters are affected, but none of the descendants of the first-generation son. In the third generation, all children of the affected second-generation women are affected, but none of the descendants of the second-generation men. What is the most likely mode of inheritance?

Accepted Answer

Mitochondrial

Answer

Autosomal dominant

Answer

Autosomal recessive

Answer

X-linked dominant

Question 4

Which of the following is NOT an autosomal dominant disorder?

Accepted Answer

Alkaptonurea

Answer

Hereditary spherocytosis

Answer

Osteogenesis imperfecta

Answer

Gardner syndrome

Question 5

BRCA-1 gene is located on which chromosome?

Accepted Answer

Chromosome 17

Answer

Chromosome 13

Answer

Chromosome 11

Answer

Chromosome 22

Question 6

The chromosomal karyotype in Patau syndrome is?

Accepted Answer

47XX,+13

Answer

47,+21

Answer

46XX/47,+18

Answer

45XX,der(14;21)

Question 7

Myotonic dystrophy is due to which genetic abnormality?

Accepted Answer

CTG trinucleotide repeat mutation

Answer

Expansion in a coding region

Answer

CAG trinucleotide repeat mutation

Answer

Mutation involving chromosome 15

Question 8

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?

Accepted Answer

46, XXY

Answer

45, XYY

Answer

46, XY

Answer

46, X

Question 9

Which of the following exhibits allelic heterogeneity?

Accepted Answer

Beta-thalassemia

Answer

Sickle cell disease

Answer

HOCM

Answer

Duchenne muscular dystrophy

Question 10

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

Accepted Answer

1 in 1

Answer

1 in 4

Answer

1 in 2

Answer

1 in 3

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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