Molecular Pathology Practice Questions

Q: Angelman syndrome is caused by:

Maternal imprinting. **Explanation:** Angelman syndrome is a classic example of **Genomic Imprinting**, an epigenetic process where certain genes are expressed in a parent-of-origin-specific manner [1]. **1. Why Maternal Imprinting is Correct:** In normal individuals, the **UBE3A gene** on chromosome 15 (15q11-q13) is active only on the maternal chromosome, while the paternal copy is silenced (imprinted). Angelman syndrome occurs when the **maternal** contribution is lost—either through a deletion of the maternal 15q11-q13 region (70% of cases), paternal uniparental disomy (two copies from the father), or imprinting defects [1]. Because the paternal gene is already silenced, the loss of the functional maternal gene leads to a total lack of UBE3A expression in the brain. **2. Why Other Options are Incorrect:** * **Paternal Imprinting:** This refers to the silencing of the paternal allele. If the **paternal** contribution is lost (and the maternal copy is silenced), it results in **Prader-Willi Syndrome**, not Angelman [1]. * **Both/None:** These are incorrect as the syndromes are distinct clinical entities based on which parental allele is defective [1]. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic:** **M**aternal = **A**ngelman (**M**appy **A**ngel); **P**aternal = **P**rader-Willi (**P**opular **P**rader). * **Angelman Presentation:** "Happy Puppet" syndrome—characterized by inappropriate laughter, seizures, ataxia, and severe intellectual disability [1]. * **Prader-Willi Presentation:** Hyperphagia (obesity), hypogonadism, and hypotonia [1]. * **Diagnosis:** Fluorescence in situ hybridization (FISH) or methylation-specific PCR [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 181-182.

Q: A particular genetic disorder appears in three consecutive generations of a family without any sex predilection. It was also noticed that phenotypically normal family members were having healthy offspring. What is the pattern of inheritance of this disorder?

Autosomal dominant. ### Explanation The correct answer is **Autosomal Dominant (AD)**. This conclusion is based on three key inheritance patterns described in the clinical vignette: 1. **Vertical Transmission:** The disorder appears in three consecutive generations. This "vertical" pattern is a hallmark of AD inheritance, where the disease does not skip generations. 2. **No Sex Predilection:** The disorder affects males and females equally, indicating an **Autosomal** rather than a sex-linked (X-linked) pattern. 3. **Lack of Carrier State:** The fact that phenotypically normal family members have healthy offspring confirms that the trait is dominant. In AD disorders, individuals who do not express the phenotype (aa) do not carry the pathological allele and therefore cannot pass it to their children. [1] #### Why other options are incorrect: * **Autosomal Recessive:** Typically shows a **horizontal inheritance** pattern (affecting siblings). It often skips generations, and phenotypically normal parents can be carriers (Aa) and produce affected offspring. * **Mitochondrial Inheritance:** This follows a **maternal inheritance** pattern. An affected mother passes the trait to *all* her children, but an affected father passes it to *none*. * **Uniparental Disomy (UPD):** This occurs when a person receives two copies of a chromosome from one parent and none from the other (e.g., Prader-Willi or Angelman syndromes). #### High-Yield Clinical Pearls for NEET-PG: * **AD Rule of 50:** An affected individual (Aa) has a **50% chance** of passing the trait to each offspring. * **Exceptions to AD rules:** Always look for terms like **Incomplete Penetrance** (has the gene but not the disease) and **Variable Expressivity** (different severity in the same family). [1] * **Structural vs. Metabolic:** Most AD disorders involve **structural proteins** (e.g., Marfan syndrome, Achondroplasia), whereas most AR disorders involve **enzyme deficiencies**. [2]

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.

Question 1

A female patient's karyotype is shown. What is the expected clinical abnormality?

Accepted Answer

Turner syndrome

Answer

Kallman syndrome

Answer

Androgen insensitivity syndrome

Answer

Down syndrome

Question 2

In an autosomal recessive disorder, if one parent is normal and the other is a carrier, and the child is affected, what is the genetic mechanism responsible?

Accepted Answer

Uniparental disomy

Answer

Germline mosaicism

Answer

Genomic imprinting

Answer

Incomplete penetrance

Question 3

Which of the following is true regarding Turner syndrome?

Accepted Answer

Preductal coarctation of aorta

Answer

XY chromosomal abnormality

Answer

Tall stature, small testes

Answer

Presence of testes

Question 4

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 occurrence of two affected children in this family?

Accepted Answer

Germline mosaicism

Answer

Non-penetrance

Answer

Uniparental disomy

Answer

Genomic imprinting

Question 5

Males who are sexually underdeveloped with rudimentary testes and prostate glands, sparse pubic and facial hair, long arms and legs and large hands & feet are likely to have which chromosomal abnormality?

Accepted Answer

46, XXY

Answer

45, XYY

Answer

46, XY

Answer

46, X

Question 6

Angelman syndrome is caused by:

Accepted Answer

Maternal imprinting

Answer

Paternal imprinting

Answer

Both of the above

Answer

None of the above

Question 7

Which of the following tests is not used for the detection of specific aneuploidy?

Accepted Answer

Microarray

Answer

FISH

Answer

None

Answer

QF-PCR

Question 8

A particular genetic disorder appears in three consecutive generations of a family without any sex predilection. It was also noticed that phenotypically normal family members were having healthy offspring. What is the pattern of inheritance of this disorder?

Accepted Answer

Autosomal dominant

Answer

Autosomal recessive

Answer

Mitochondrial inheritance

Answer

Uniparental disomy

Question 9

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 10

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

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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