Molecular Pathology Practice Questions

Q: Paternal 15 chromosome deletion is seen in which of the following conditions?

Prader Willi syndrome. This question tests the concept of **Genomic Imprinting**, an epigenetic phenomenon where certain genes are expressed in a parent-of-origin-specific manner [1]. ### **Explanation of the Correct Answer** **Prader-Willi Syndrome (PWS)** occurs due to the loss of function of genes in the **15q11-q13** region on the **paternal chromosome** [1]. In normal individuals, the maternal copy of these specific genes is silenced (imprinted), so the individual relies solely on the paternal copy. If the paternal segment is deleted (70% of cases) or if there is Maternal Uniparental Disomy (25%), no functional genes remain, leading to the syndrome. * **Clinical Presentation:** Neonatal hypotonia, hyperphagia leading to morbid obesity, hypogonadism, and small hands/feet. ### **Analysis of Incorrect Options** * **A. Angelman Syndrome:** This is the "sister" condition to PWS. It involves a deletion of the same region (15q11-q13) but on the **maternal chromosome** [1]. It results in the "Happy Puppet" profile: inappropriate laughter, ataxia, and seizures [1]. * **C. Down Syndrome:** Caused by **Trisomy 21**. It is a numerical chromosomal aberration, not related to imprinting or chromosome 15. * **D. Turner Syndrome:** Caused by **Monosomy X (45, XO)**. It is characterized by short stature, webbed neck, and streak ovaries. ### **High-Yield Clinical Pearls for NEET-PG** * **Mnemonic:** **P**ader-Willi = **P**aternal deletion; **A**ngelman = **M**aternal deletion (**MAP**: Maternal Angelman Prader). * **Uniparental Disomy (UPD):** PWS can also be caused by inheriting two copies of chromosome 15 from the mother (Maternal UPD) and none from the father. * **Diagnosis:** The gold standard screening test for both syndromes is **DNA Methylation Analysis** [1]. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 181-183.

Q: What is the most common group of diseases following Mendelian inheritance?

Autosomal dominant. **Explanation:** The correct answer is **Autosomal dominant (AD)**. In the context of Mendelian (monogenic) inheritance, autosomal dominant disorders represent the most common group of inherited diseases. This is primarily because AD traits are expressed in the heterozygous state; an individual only needs one copy of the mutant allele to manifest the disease. **Why Autosomal Dominant is correct:** Statistically, AD disorders occur more frequently in the general population compared to recessive ones. Many AD conditions involve mutations in genes encoding **structural proteins** (e.g., Collagen in Osteogenesis Imperfecta) or **regulatory proteins/receptors** (e.g., LDL receptor in Familial Hypercholesterolemia). Because these structural defects are often compatible with life until reproductive age, the alleles persist in the gene pool. **Why other options are incorrect:** * **Autosomal recessive (AR):** While AR disorders (like Cystic Fibrosis or Sickle Cell Anemia) are numerous, they require two copies of the mutant allele to manifest. This makes the clinical phenotype less frequent than AD conditions. AR disorders typically involve **enzymatic proteins**. * **X-linked recessive (XLR):** These are less common because they primarily affect males. Females are usually asymptomatic carriers. * **X-linked dominant (XLD):** This is the rarest form of Mendelian inheritance (e.g., Vitamin D-resistant rickets). **High-Yield Clinical Pearls for NEET-PG:** * **Most common AD disorder:** Familial Hypercholesterolemia. * **Most common AR disorder (Global):** Thalassemia. * **Key Concept:** AD disorders often show **pleiotropy** (one gene affecting multiple systems) and **variable expressivity** (varying severity among individuals). * **Rule of Thumb:** Structural protein defect → Autosomal Dominant; Enzyme deficiency → Autosomal Recessive.

Q: ATM mutation is seen in which of the following conditions?

Ataxia telangiectasia. **Explanation:** **1. Why Ataxia Telangiectasia is correct:** Ataxia Telangiectasia (AT) is an autosomal recessive multisystem disorder caused by mutations in the **ATM (Ataxia-Telangiectasia Mutated) gene** located on **chromosome 11q22-23**. The ATM protein is a critical serine/threonine kinase that senses **double-stranded DNA breaks** [1]. Upon detecting damage, it activates p53 and other checkpoint proteins to halt the cell cycle or initiate repair. A mutation leads to genomic instability, clinical ataxia, oculocutaneous telangiectasia, and profound radiosensitivity [1]. **2. Why the other options are incorrect:** * **Fragile X Syndrome:** Caused by a **CGG trinucleotide repeat expansion** in the **FMR1 gene** on the X chromosome, leading to hypermethylation and gene silencing. * **Joubert Syndrome:** A ciliopathy characterized by the "molar tooth sign" on MRI. It is genetically heterogeneous, involving mutations in genes like **INPP5E or TMEM67**, but not ATM. * **Spinocerebellar Ataxia (SCA):** Most common forms (SCA1, 2, 3) are caused by **CAG trinucleotide repeats** (polyglutamine diseases) in various genes (e.g., ATXN1), not ATM [1]. **3. High-Yield Clinical Pearls for NEET-PG:** * **Classic Triad:** Progressive cerebellar ataxia, oculocutaneous telangiectasias, and recurrent sinopulmonary infections (due to **IgA deficiency**). * **Laboratory Marker:** Characteristically elevated **Alpha-Fetoprotein (AFP)** levels in children. * **Malignancy Risk:** Patients have a 100-fold increased risk of developing lymphomas and leukemias. * **Diagnostic Hallmark:** Increased sensitivity to **ionizing radiation** (due to defective DNA repair). **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. The Central Nervous System, pp. 1300-1301.

Q: Analyze the provided pedigree chart to identify the underlying genetic disease.

Crouzon syndrome. ***Crouzon syndrome*** - Shows **autosomal dominant inheritance** pattern with multiple generations affected, both sexes involved, and approximately **50% of offspring** affected. - Exhibits **father-to-son transmission**, which is characteristic of autosomal dominant conditions and excludes X-linked inheritance. *Sickle cell anaemia* - Follows **autosomal recessive inheritance** where typically only one generation is affected with unaffected parents having affected children. - Would require **both parents to be carriers** and show a **25% recurrence risk** in offspring, not the pattern seen in the pedigree. *Diabetes insipidus* - Most forms are **acquired** rather than inherited, and when hereditary, usually show **autosomal dominant** or **X-linked recessive** patterns. - **Nephrogenic diabetes insipidus** (X-linked) would show male predominance with no father-to-son transmission, inconsistent with this pedigree. *Hunter syndrome* - Exhibits **X-linked recessive inheritance** with affected males and carrier females, showing a distinctive pattern. - Would demonstrate **no father-to-son transmission** and predominantly affect males through carrier mothers, unlike the pedigree shown.

Question 1

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?

Accepted Answer

Germline mosaicism

Answer

Non-penetrance

Answer

Uniparental disomy

Answer

Genomic imprinting

Question 2

In an Autosomal Recessive (AR) disorder, if one parent is normal and the other is a carrier, and the child is affected, what is the most likely explanation for this inheritance pattern?

Accepted Answer

Uniparental disomy

Answer

Germline mosaicism

Answer

Genomic imprinting

Answer

Mitochondrial inheritance

Question 3

Paternal 15 chromosome deletion is seen in which of the following conditions?

Accepted Answer

Prader Willi syndrome

Answer

Angelman syndrome

Answer

Down syndrome

Answer

Turner syndrome

Question 4

Which one of the following disorders is autosomal recessive?

Accepted Answer

Tay-Sachs disease

Answer

Adult polycystic kidney disease

Answer

Marfan syndrome

Answer

Familial hypercholesterolemia

Question 5

Bifid ribs, multiple radiolucent lesions of the jaws, multiple basal cell nevi, and falx cerebri calcification are found in which condition?

Accepted Answer

Basal cell nevus syndrome

Answer

Sturge Weber syndrome

Answer

Horner syndrome

Answer

Hereditary internal polyposis

Question 6

All of the following may be associated with Von Hippel-Lindau syndrome, except?

Accepted Answer

Gastric carcinoma

Answer

Retinal and cerebellar hemangioblastomas

Answer

Pheochromocytoma

Answer

Renal cell carcinoma

Question 7

What is the most common group of diseases following Mendelian inheritance?

Accepted Answer

Autosomal dominant

Answer

Autosomal recessive

Answer

X-linked dominant

Answer

X-linked recessive

Question 8

ATM mutation is seen in which of the following conditions?

Accepted Answer

Ataxia telangiectasia

Answer

Fragile X syndrome

Answer

Joubert syndrome

Answer

Spinocerebellar ataxia

Question 9

Analyze the provided pedigree chart to identify the underlying genetic disease.

Accepted Answer

Crouzon syndrome

Answer

Sickle cell anaemia

Answer

Diabetes insipidus

Answer

Hunter syndrome

Question 10

What is the most common tumor in females with tuberous sclerosis?

Accepted Answer

Angiomyolipoma

Answer

Rhabdomyosarcoma

Answer

Pulmonary lymphangioleiomyomatosis

Answer

Optic glioma

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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