Molecular Pathology Practice Questions

Q: What is the genetic abnormality in fragile X-syndrome?

Trinucleotide repeat disorder.. Fragile X Syndrome is the most common cause of inherited intellectual disability and the most common monogenic cause of autism. **Why Option A is correct:** The condition is a classic example of a **Trinucleotide Repeat Disorder** [1]. It is caused by the expansion of a **CGG repeat** in the 5' untranslated region of the **FMR1 gene** located on the X chromosome (Xq27.3) [1]. * **Normal:** 200 repeats. This expansion leads to hypermethylation of the promoter region, silencing the gene and resulting in a deficiency of the Fragile X Mental Retardation Protein (FMRP), which is essential for neural development. **Why other options are incorrect:** * **Option B (Point mutation):** While point mutations can occur in the FMR1 gene, they account for <1% of cases. The hallmark of the syndrome is the triplet expansion. * **Option C (Not inheritable):** This is incorrect; it follows an **X-linked dominant** inheritance pattern with variable expressivity and reduced penetrance in females. * **Option D (Deletion):** Large deletions of the FMR1 gene are rare causes. The primary mechanism is expansion, not loss of a chromosomal segment [1]. **High-Yield Clinical Pearls for NEET-PG:** * **Anticipation:** The disease severity increases and age of onset decreases in successive generations (occurs during maternal meiosis). * **Clinical Triad:** Long face with a prominent jaw (prognathism), large everted ears, and **macro-orchidism** (post-pubertal). * **Cytogenetics:** When cells are cultured in a folate-deficient medium, the X chromosome shows a "fragile site" (breakage) at the distal end of the long arm. * **Diagnosis:** PCR (for small expansions) and **Southern Blot** (to confirm full mutations and methylation status).

Q: Which one of the following conditions is not autosomal recessive?

Neurofibromatosis. **Explanation:** The correct answer is **Neurofibromatosis**, as it follows an **Autosomal Dominant (AD)** inheritance pattern, whereas the other listed conditions are Autosomal Recessive (AR). **1. Why Neurofibromatosis is the correct answer:** Neurofibromatosis (both Type 1 and Type 2) is a classic example of an Autosomal Dominant disorder. * **NF1 (von Recklinghausen disease):** Caused by a mutation in the *NF1* gene on **Chromosome 17** (encodes Neurofibromin). * **NF2:** Caused by a mutation in the *NF2* gene on **Chromosome 22** (encodes Merlin). A key feature of NF is **100% penetrance** but **variable expressivity**, meaning everyone with the gene will show symptoms, but the severity varies widely. **2. Analysis of Incorrect Options (AR Disorders):** * **Cystic Fibrosis:** The most common lethal AR disorder in Caucasians, caused by a mutation in the *CFTR* gene on Chromosome 7. * **Wilson’s Disease:** An AR disorder of copper metabolism due to mutations in the *ATP7B* gene on Chromosome 13. * **Hemochromatosis:** Most commonly an AR disorder (HFE gene mutation on Chromosome 6) leading to iron overload. **3. NEET-PG High-Yield Clinical Pearls:** * **Mnemonic for AR:** "Most enzyme deficiencies are AR" (except Hunter syndrome and Fabry disease). * **Mnemonic for AD:** "Structural protein defects are usually AD" (e.g., Marfan, Achondroplasia, NF). * **NF1 Clinical Triad:** Café-au-lait spots, Lisch nodules (iris hamartomas), and Neurofibromas. * **NF2 Clinical Hallmark:** Bilateral Acoustic Neuromas (Vestibular Schwannomas) [1].

Q: List the odd one out among the following:

Trisomy 18 (Noonan syndrome). **Explanation:** The core concept of this question lies in identifying the correct association between chromosomal aneuploidies and their clinical eponyms. **Why Option A is the Correct Answer (The "Odd One Out"):** Option A is factually incorrect and represents a mismatch. **Trisomy 18** is clinically known as **Edwards syndrome**, not Noonan syndrome. **Noonan syndrome** is an autosomal dominant genetic disorder (often involving mutations in the *PTPN11* gene) characterized by short stature, heart defects (pulmonic stenosis), and webbed neck. It is often referred to as the "male version of Turner syndrome" but occurs in both sexes with a normal karyotype. **Analysis of Incorrect Options (Correct Associations):** * **Option B: Trisomy 21 (Down syndrome):** This is the most common autosomal trisomy [1]. Key features include Simian crease, mental retardation, and Brushfield spots [1]. * **Option C: Trisomy 18 (Edwards syndrome):** This is the second most common autosomal trisomy. Key features include "rocker-bottom" feet, clenched fists with overlapping fingers, and micrognathia. * **Option D: Trisomy 13 (Patau syndrome):** Characterized by midline defects such as holoprosencephaly, cleft lip/palate, and polydactyly. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for Trisomies:** **P**atau (13 - **P**uberty age), **E**dwards (18 - **E**lection age), **D**own (21 - **D**rinking age). * **Maternal Screening:** In Down syndrome, HCG and Inhibin-A are **increased**, while AFP and Estriol are **decreased**. In Edwards syndrome, all four markers are typically decreased. * **Noonan vs. Turner:** Noonan syndrome presents with **Pulmonic Stenosis**, whereas Turner syndrome (45,XO) is associated with **Coarctation of the Aorta** [2].

Q: Which of the following is NOT a characteristic of Turner syndrome?

True hermaphrodism. **Explanation:** **Turner Syndrome (45,X)** is the most common sex chromosome abnormality in females, characterized by the complete or partial absence of one X chromosome [1]. **Why "True Hermaphroditism" is the correct answer:** True Hermaphroditism (now termed **Ovotesticular Disorder of Sex Development**) is defined by the presence of both ovarian and testicular tissue in the same individual. Turner syndrome patients, however, do not possess testicular tissue. Instead, they have **"streak ovaries"** (dysgenetic gonads) where follicles are absent and replaced by fibrous stroma [1]. They are phenotypically female but remain sexually infantile. **Why the other options are incorrect:** * **Short Stature:** This is the most consistent clinical feature of Turner syndrome, primarily due to the haploinsufficiency of the **SHOX gene** located on the short arm of the X chromosome [1]. * **Webbed Neck (Cystic Hygroma/Pterygium colli):** This results from lymphatic obstruction during fetal development. Other related features include a low posterior hairline and a broad "shield-shaped" chest [1]. * **Dysgenetic Gonads:** As mentioned, accelerated oocyte loss leads to fibrous "streak" ovaries, resulting in primary amenorrhea and infertility. **High-Yield Clinical Pearls for NEET-PG:** * **Karyotype:** 45,X is the most common (50%), but mosaics (e.g., 45,X/46,XX) and structural abnormalities (Isochromosome Xq) also occur [1]. * **Cardiac Associations:** Bicuspid aortic valve (most common) and Coarctation of the aorta (pre-ductal). * **Renal Association:** Horseshoe kidney. * **Biochemical Markers:** Elevated LH and FSH levels (Hypergonadotropic hypogonadism) due to lack of feedback inhibition from estrogen. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Genetic Disorders, pp. 175-177.

Q: Which of the following is NOT a single gene disorder?

William's syndrome. **Explanation:** The distinction between single-gene (monogenic) disorders and chromosomal microdeletion syndromes is a high-yield concept for NEET-PG [2]. **Why William’s Syndrome is the correct answer:** Unlike the other options, **William’s Syndrome** is not caused by a mutation in a single gene. It is a **microdeletion syndrome** caused by a contiguous gene deletion on the long arm of **chromosome 7 (7q11.23)** [2]. This deletion involves approximately 26–28 genes, including the *ELN* (elastin) gene. Because it involves the loss of multiple neighboring genes rather than a single point mutation or triplet repeat, it is classified as a chromosomal disorder. **Why the other options are incorrect:** * **Hemochromatosis (Option A):** An autosomal recessive single-gene disorder, most commonly due to a mutation in the **HFE gene** (C282Y or H63D). * **Cystic Fibrosis (Option B):** A classic autosomal recessive single-gene disorder caused by mutations in the **CFTR gene** on chromosome 7. * **Huntington’s Disease (Option D):** An autosomal dominant single-gene disorder caused by a **CAG trinucleotide repeat expansion** in the *HTT* gene on chromosome 4. **Clinical Pearls for NEET-PG:** * **William’s Syndrome Triad:** "Elfin" facies, Intellectual disability (with "cocktail party" personality/extreme loquacity), and Cardiovascular defects (most commonly **Supravalvular Aortic Stenosis**) [1]. * **Diagnosis:** The gold standard for detecting microdeletions like William’s is **FISH** (Fluorescence In Situ Hybridization) or Chromosomal Microarray [2]. * **Metabolic association:** Idiopathic **infantile hypercalcemia** is a characteristic feature of William’s syndrome.

Question 1

What is the genetic abnormality in fragile X-syndrome?

Accepted Answer

Trinucleotide repeat disorder.

Answer

Point mutation

Answer

Not inheritable

Answer

Deletion

Question 2

Deletion of chromosome 11 is associated with which of the following conditions?

Accepted Answer

Wilms tumor

Answer

Neuroblastoma

Answer

Retinoblastoma

Answer

Osteosarcoma

Question 3

A normal parent has two siblings with osteogenesis imperfecta. What is the most likely pattern of inheritance?

Accepted Answer

Germline mosaicism

Answer

Mutation

Answer

Anticipation

Answer

Genomic imprinting

Question 4

Which one of the following conditions is not autosomal recessive?

Accepted Answer

Neurofibromatosis

Answer

Cystic fibrosis

Answer

Wilson's disease

Answer

Hemochromatosis

Question 5

What chromosomal reason can explain autosomal recessive disorders in a child when one parent is unaffected and the other is a carrier?

Accepted Answer

Uniparental disomy

Answer

Germline mosaicism

Answer

Genomic imprinting

Answer

Incomplete penetrance

Question 6

Chromosomal non-disjunction is responsible for all of the following conditions EXCEPT:

Accepted Answer

Neurofibromatosis type 1

Answer

Down's syndrome

Answer

Prader-Willi syndrome

Answer

Angelman syndrome

Question 7

List the odd one out among the following:

Accepted Answer

Trisomy 18 (Noonan syndrome)

Answer

Trisomy 21 (Down syndrome)

Answer

Trisomy 18 (Edwards syndrome)

Answer

Trisomy 13 (Patau syndrome)

Question 8

Which of the following is NOT a characteristic of Turner syndrome?

Accepted Answer

True hermaphrodism

Answer

Short stature

Answer

Webbed neck

Answer

Dysgenetic gonads

Question 9

Which of the following features is not characteristic of Fragile X syndrome?

Accepted Answer

Micro-orchidism

Answer

Hyperextensible joints

Answer

Small nose

Answer

Mental retardation

Question 10

Which of the following is NOT a single gene disorder?

Accepted Answer

William's syndrome

Answer

Hemochromatosis

Answer

Cystic fibrosis

Answer

Huntington's disease

Molecular Pathology — MCQs

Molecular Pathology — MCQs

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