Genetics and Disease Practice Questions

Q: A family pedigree reveals first- and second-generation female relatives with premature menopause and male relatives with a progressive neurodegenerative disorder starting by their sixth decade. There are more males than females exhibiting mental retardation from childhood by the fourth generation. Genetic analysis of affected persons reveals CGG repeat expansions in a gene encoding for a protein that binds mRNA transcripts in neurons and shuttles them to the synapses. An abnormality involving which of the following organs is most likely to be present in affected males?

Testis. ### Explanation The clinical scenario describes **Fragile X Syndrome (FXS)** and its associated premutation syndromes, caused by a **CGG trinucleotide repeat expansion** in the **FMR1 gene** (Xq27.3). This gene encodes the **FMRP protein**, which regulates mRNA transport to synapses. **Why Testis is Correct:** The hallmark physical finding in post-pubertal males with Fragile X Syndrome is **macroorchidism** (enlarged testes). This occurs due to an increase in interstitial fluid and connective tissue. The pedigree also highlights the "anticipation" and "premutation" phenotypes: * **Premature Menopause:** Known as Fragile X-associated Primary Ovarian Insufficiency (FXPOI) in female premutation carriers (55–200 repeats). * **Neurodegenerative Disorder:** Known as Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) in older male premutation carriers. * **Mental Retardation:** The full mutation (>200 repeats) leads to transcriptional silencing of FMR1, causing the classic intellectual disability syndrome [2]. **Why Incorrect Options are Wrong:** * **Adrenal/Pituitary:** While FXS involves the hypothalamic-pituitary-gonadal axis [3], there are no characteristic structural or functional abnormalities of the adrenal or pituitary glands associated with FMR1 mutations. * **Pancreas:** Pancreatic pathology is not a feature of Fragile X. Diabetes or exocrine insufficiency is not linked to CGG repeat expansions. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** X-linked Dominant with variable expressivity (due to Lyonization in females). * **Cytogenetics:** Seen as a "break" or "fragile site" at the end of the X chromosome when cultured in folate-deficient medium. * **Physical Features:** Long face, large everted ears, prominent jaw (prognathism), and mitral valve prolapse. * **Behavioral:** Most common inherited cause of intellectual disability and a leading genetic cause of Autism [1].

Q: Which of the following diseases is NOT caused by a point mutation?

Hereditary sensory and motor neuropathy type 1. ### Explanation The correct answer is **Hereditary Sensory and Motor Neuropathy Type 1 (HSMN-1)**, also known as **Charcot-Marie-Tooth disease type 1A (CMT1A)**. **1. Why HSMN-1 is the correct answer:** Unlike the other options, CMT1A is typically caused by a **large-scale DNA duplication**, not a point mutation. Specifically, it involves a **1.5 Mb duplication** of the **PMP22 gene** on chromosome 17. This leads to an overexpression of the peripheral myelin protein 22, resulting in abnormal myelin structure and function. **2. Why the other options are incorrect:** * **Hemochromatosis:** Most commonly caused by a point mutation in the **HFE gene** (C282Y or H63D), where a single nucleotide change leads to an amino acid substitution [1]. * **Achondroplasia:** This is the most common cause of dwarfism and is caused by a specific point mutation in the **FGFR3 gene** (G380R), leading to a gain-of-function [2]. * **Alpha-1 Antitrypsin Deficiency:** The most severe form (PiZZ) is caused by a single point mutation (Glu342Lys) in the **SERPINA1 gene**, causing protein misfolding and accumulation in the liver [1]. ### NEET-PG Clinical Pearls * **CMT1A (HSMN-1):** Look for "stork leg" or "inverted champagne bottle" appearance of legs, pes cavus, and "onion bulb" formation on nerve biopsy due to repeated demyelination and remyelination. * **Achondroplasia:** 80% of cases are due to *de novo* mutations, often associated with advanced paternal age [2]. * **Point Mutations vs. Repeat Expansions:** Remember that Huntington’s and Fragile X are caused by **trinucleotide repeat expansions**, while CMT1A is a **duplication**. These are high-yield distinctions for "not a point mutation" questions [3].

Q: A 22-year-old man presents with arm span greater than height, subluxed lenses, and dilation of the aorta. What is the most likely diagnosis?

Marfan syndrome. **Explanation:** The clinical triad of **skeletal abnormalities** (arm span > height), **ectopia lentis** (subluxed lenses), and **aortic root dilation** is the classic presentation of **Marfan Syndrome** [1]. **1. Why Marfan Syndrome is Correct:** Marfan syndrome is an **autosomal dominant** connective tissue disorder caused by a mutation in the **FBN1 gene** on chromosome 15, which encodes **Fibrillin-1** [1]. Fibrillin-1 is essential for the structural integrity of the extracellular matrix and the regulation of TGF-β. * **Skeletal:** Patients exhibit a "marfanoid habitus" (tall stature, arachnodactyly, and an increased arm span-to-height ratio). * **Ocular:** Upward and outward (superotemporal) subluxation of the lens is a hallmark. * **Cardiovascular:** Cystic medial necrosis leads to aortic root dilation, which can progress to aortic dissection—the most common cause of mortality [1]. **2. Why Other Options are Incorrect:** * **Ehlers-Danlos Syndrome:** Characterized by skin hyperextensibility and joint hypermobility. While it involves vascular issues, it typically lacks the tall stature and specific lens subluxation seen here. * **Werner Syndrome:** A rare progeroid (premature aging) syndrome characterized by short stature, cataracts, and skin changes, not marfanoid features. * **Laurence-Moon-Biedl Syndrome:** A ciliopathy presenting with obesity, retinitis pigmentosa, polydactyly, and hypogonadism. **NEET-PG High-Yield Pearls:** * **Lens Subluxation:** Marfan = **Upward** (Superior); Homocystinuria = **Downward** (Interior). * **Diagnosis:** Based on the **Ghent Criteria**. * **Management:** Beta-blockers or ARBs (Losartan) are used to slow the rate of aortic dilation. * **Most common cause of death:** Aortic dissection/rupture [1].

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

Homocystinuria. **Explanation:** **Homocystinuria (Option A)** is the correct answer. It is an **autosomal recessive (AR)** metabolic disorder, most commonly caused by a deficiency of the enzyme **cystathionine beta-synthase (CBS)**. In NEET-PG, a high-yield rule of thumb is that almost all **inborn errors of metabolism** (enzyme deficiencies) follow an autosomal recessive inheritance pattern [1] (exceptions include Hunter syndrome and Fabry disease). **Analysis of Incorrect Options:** * **G6PD Deficiency (Option B):** This is an **X-linked recessive** condition. It is the most common red cell enzyme deficiency worldwide, leading to episodic hemolysis under oxidative stress. * **Myotonic Dystrophy (Option C):** This follows an **autosomal dominant** pattern. It is characterized by "anticipation" due to CTG trinucleotide repeat expansions on chromosome 19. * **Otospongiosis/Otosclerosis (Option D):** This is typically inherited in an **autosomal dominant** pattern with variable penetrance. It is a common cause of progressive conductive hearing loss in young adults. **Clinical Pearls for NEET-PG:** * **Homocystinuria vs. Marfan Syndrome:** Both present with tall stature and arachnodactyly. However, Homocystinuria features **downward (inferomedial)** lens subluxation, intellectual disability, and a high risk of **thromboembolism**. Marfan syndrome features upward (superotemporal) ectopia lentis and normal intelligence. * **Diagnosis:** Screened via the **Cyanide-nitroprusside test** (positive urine test). * **Treatment:** A subset of patients responds to high doses of **Vitamin B6 (Pyridoxine)**, which acts as a cofactor for the CBS enzyme [2].

Q: Which of the following is an autosomal dominant metabolic disorder?

Familial hypercholesterolemia. The correct answer is **Familial Hypercholesterolemia (FH)**. **1. Why Familial Hypercholesterolemia is correct:** FH is a classic example of an **Autosomal Dominant (AD)** metabolic disorder [1]. It is primarily caused by mutations in the **LDLR gene** (encoding the LDL receptor), though mutations in *APOB* or *PCSK9* can also be responsible [1]. Because it is dominant, even heterozygotes (1 in 250 individuals) have significantly elevated LDL levels from birth, leading to premature atherosclerosis and tendon xanthomas [1]. **2. Why the other options are incorrect:** * **Cystic Fibrosis (A):** This is the most common lethal **Autosomal Recessive (AR)** disorder in Caucasians, caused by mutations in the *CFTR* gene. * **Phenylketonuria (B):** This is an **Autosomal Recessive** inborn error of metabolism involving a deficiency of the enzyme phenylalanine hydroxylase. * **Alpha-1 Antitrypsin Deficiency (C):** This follows an **Autosomal Recessive** (or more accurately, co-dominant) inheritance pattern. It typically presents with early-onset emphysema and liver cirrhosis. **3. NEET-PG High-Yield Pearls:** * **Rule of Thumb:** Most **enzymatic** deficiencies are Autosomal Recessive, whereas disorders involving **structural proteins or receptors** (like the LDL receptor in FH) are often Autosomal Dominant. * **Clinical Triad of FH:** Elevated LDL-C, Tendon Xanthomas (especially the Achilles tendon), and Arcus Senilis at a young age. * **Other AD Metabolic/Structural Disorders to remember:** Marfan Syndrome, Huntington’s Disease, Neurofibromatosis, and Adult Polycystic Kidney Disease (ADPKD).

Q: Edwards syndrome is associated with which chromosomal abnormality?

Trisomy 18. **Explanation:** **Edwards syndrome** is caused by **Trisomy 18** (an extra copy of chromosome 18). It is the second most common autosomal trisomy among live births, following Down syndrome. The condition is characterized by severe intellectual disability and multi-system defects, with a high mortality rate in the first year of life. **Analysis of Options:** * **Option A (Trisomy 21):** This is **Down syndrome**, the most common chromosomal disorder. Key features include Brushfield spots, simian crease, and increased risk of Alzheimer’s and ALL. * **Option C (Trisomy 13):** This is **Patau syndrome**. It is clinically distinguished by "midline defects" such as holoprosencephaly, cleft lip/palate, and polydactyly. * **Option D (5p deletion):** This is **Cri-du-chat syndrome**. It is characterized by a high-pitched, cat-like cry, microcephaly, and severe developmental delay. **Clinical Pearls for NEET-PG:** To differentiate the trisomies quickly, remember these high-yield physical findings for Edwards syndrome: 1. **Clenched fists** with overlapping fingers (index finger over 3rd, 5th over 4th). 2. **Rocker-bottom feet** (also seen in Patau, but classic for Edwards). 3. **Micrognathia** (small jaw) and low-set malformed ears. 4. **Congenital Heart Disease:** Most commonly VSD or PDA. 5. **Prenatal Screening:** Shows decreased levels of MS-AFP, hCG, and unconjugated estriol (uE3). **Mnemonic:** "Edwards" starts with **E**, and **E**ighteen starts with **E**. Also, think of **E**lection age (18) to remember Trisomy 18.

Q: Adrenomyeloneuropathy, a variant of adrenoleukodystrophy which manifests as adrenal insufficiency beginning in childhood and later develops into a progressive spastic paraparesis, is transmitted as:

X-linked disorder. **Explanation:** **Adrenoleukodystrophy (ALD)** and its adult-onset variant, **Adrenomyeloneuropathy (AMN)**, are caused by mutations in the ***ABCD1* gene** located on the **X chromosome**. This gene encodes the adrenoleukodystrophy protein (ALDP), a peroxisomal membrane transporter required for the breakdown of **Very Long Chain Fatty Acids (VLCFA)**. 1. **Why X-linked is correct:** The *ABCD1* mutation leads to the accumulation of VLCFAs in the plasma and tissues, specifically the adrenal cortex and the white matter of the CNS. Because the gene is located on the X chromosome, the disease follows an **X-linked recessive** inheritance pattern. It primarily affects males, while female carriers may develop milder neurological symptoms later in life. 2. **Why other options are incorrect:** * **Autosomal Dominant/Recessive:** Peroxisomal biogenesis disorders like Zellweger Syndrome are autosomal recessive, but ALD/AMN is strictly linked to the X chromosome. * **Sporadic:** While *de novo* mutations can occur, the condition is a heritable genetic disorder with a predictable transmission pattern. **Clinical Pearls for NEET-PG:** * **Classic Presentation:** A young boy with behavioral changes, vision loss, and skin hyperpigmentation (due to adrenal insufficiency/Addison’s disease). * **AMN Variant:** Presents in the 20s-40s with progressive spastic paraparesis and sphincter dysfunction. * **Diagnosis:** Elevated plasma levels of **VLCFA** (most specific test). * **MRI Finding:** Symmetrical enhancement of the posterior white matter (occipito-parietal region). * **Treatment:** Dietary restriction is ineffective; Hematopoietic Stem Cell Transplant (HSCT) is the treatment of choice in early stages.

Q: Fredrich's ataxia is caused by which type of mutation?

Expanded trinucleotide repeat. **Explanation:** **Friedreich's Ataxia (FRDA)** is an autosomal recessive neurodegenerative disorder. The correct answer is **Expanded Trinucleotide Repeat** because the disease is caused by an unstable expansion of the **GAA** triplet repeat in the first intron of the **FXN gene** on chromosome 9. This expansion leads to transcriptional silencing (epigenetic knockdown) of the gene, resulting in a deficiency of the protein **Frataxin**. Frataxin is essential for mitochondrial iron metabolism; its deficiency leads to iron overload in the mitochondria, causing oxidative stress and cell death, primarily in the dorsal root ganglia, spinal cord, and heart. **Analysis of Incorrect Options:** * **A & C (Point and Missense Mutations):** While point mutations (including missense) can occur in the FXN gene, they account for less than 5% of cases. The hallmark and primary cause (95%+) for NEET-PG purposes is the triplet repeat expansion. * **D (Inversion):** Inversions involve a segment of DNA being reversed end-to-end. This is the classic mechanism for **Hemophilia A** (Factor VIII gene inversion), not Friedreich's Ataxia. **High-Yield Clinical Pearls for NEET-PG:** * **Inheritance:** Autosomal Recessive (unique among most trinucleotide repeat disorders like Huntington’s or Myotonic Dystrophy, which are dominant). * **Repeat Sequence:** **GAA** (Mnemonic: Friedreich is **G**reat **A**t **A**taxia). * **Clinical Triad:** Progressive limb ataxia, loss of position/vibration sense, and absent deep tendon reflexes (especially ankle jerk). * **Most Common Cause of Death:** **Hypertrophic Cardiomyopathy** (HOCM) leading to heart failure or arrhythmias. * **Associated Findings:** Kyphoscoliosis, Pes Cavus (high-arched feet), and Diabetes Mellitus (in ~10-20% of patients).

Q: Non-frameshift mutation of the dystrophin gene causes which of the following conditions?

Becker's Muscular Dystrophy. **Explanation:** The correct answer is **Becker’s Muscular Dystrophy (BMD)**. The underlying medical concept is the **"Reading Frame Hypothesis."** 1. **Why BMD is correct:** Becker’s Muscular Dystrophy is caused by **non-frameshift mutations** (typically in-frame deletions). Because the reading frame is preserved, the cell can still produce a truncated but **partially functional** dystrophin protein. [1] This results in a milder clinical phenotype, later onset (usually >15 years), and a longer life expectancy compared to Duchenne. 2. **Why other options are incorrect:** * **Duchenne Muscular Dystrophy (DMD):** Caused by **frameshift mutations** (or nonsense mutations) that completely disrupt the reading frame. [1] This leads to a total absence of functional dystrophin, resulting in severe, progressive muscle wasting starting in early childhood. * **Myotonic Dystrophy:** This is an autosomal dominant condition caused by **triplet repeat expansions** (CTG repeats in the *DMPK* gene for Type 1), not mutations in the dystrophin gene. * **Limb Girdle Dystrophy (LGMD):** This is a heterogeneous group of disorders caused by mutations in genes encoding **sarcoglycans** [2] or other structural proteins, rather than the dystrophin gene itself. **High-Yield Clinical Pearls for NEET-PG:** * **Dystrophin Gene:** The largest known human gene (located on Xp21), making it highly susceptible to spontaneous mutations. [1] * **Gower’s Sign:** Classic clinical finding in DMD/BMD due to proximal muscle weakness. * **Diagnosis:** Gold standard is genetic testing; Muscle biopsy shows "patchy" dystrophin staining in BMD and "absent" staining in DMD. * **Cause of Death:** Most commonly due to dilated cardiomyopathy or respiratory failure.

Q: Classic form of Alport syndrome is inherited as:

X-linked. Alport syndrome is a primary glomerular disease caused by mutations in the genes encoding **Type IV collagen**, which is a critical structural component of the glomerular basement membrane (GBM), cochlea, and lens. **1. Why X-linked is Correct:** The "classic" and most common form of Alport syndrome (accounting for approximately **80-85% of cases**) is inherited in an **X-linked dominant** fashion. This is due to mutations in the **COL4A5 gene** located on the X chromosome. Because it is X-linked, males are typically more severely affected, often progressing to end-stage renal disease (ESRD), while females (heterozygotes) may have a more variable clinical course ranging from isolated hematuria to renal failure. **2. Why other options are Incorrect:** * **Autosomal Recessive (AR):** This accounts for about 15% of cases and is caused by mutations in *COL4A3* or *COL4A4*. It is seen in clinical practice but is not the "classic" or most frequent form. * **Autosomal Dominant (AD):** This is the rarest form (approx. 5%) and usually presents with a slower progression to renal failure. * **Sporadic:** While de novo mutations can occur in the *COL4A5* gene, Alport syndrome is fundamentally a hereditary genetic disorder, not a sporadic one. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Hereditary nephritis (hematuria), Sensorineural hearing loss (high frequency), and Ocular defects (**Anterior Lenticonus** is pathognomonic). * **Electron Microscopy (EM):** Characterized by a "Basket-weave appearance" due to irregular thinning and thickening of the GBM. * **Genetic Defect:** Mutation in alpha-5 chain of Type IV collagen (X-linked). * **Post-Transplant Complication:** Patients with Alport syndrome may develop **Goodpasture-like syndrome** (Anti-GBM disease) after a kidney transplant because their immune system recognizes the normal Type IV collagen in the graft as foreign.

Question 1

A family pedigree reveals first- and second-generation female relatives with premature menopause and male relatives with a progressive neurodegenerative disorder starting by their sixth decade. There are more males than females exhibiting mental retardation from childhood by the fourth generation. Genetic analysis of affected persons reveals CGG repeat expansions in a gene encoding for a protein that binds mRNA transcripts in neurons and shuttles them to the synapses. An abnormality involving which of the following organs is most likely to be present in affected males?

Accepted Answer

Testis

Answer

Adrenal

Answer

Pancreas

Answer

Pituitary

Question 2

Which of the following diseases is NOT caused by a point mutation?

Accepted Answer

Hereditary sensory and motor neuropathy type 1

Answer

Hemochromatosis

Answer

Achondroplasia

Answer

Alpha 1 antitrypsin deficiency

Question 3

A 22-year-old man presents with arm span greater than height, subluxed lenses, and dilation of the aorta. What is the most likely diagnosis?

Accepted Answer

Marfan syndrome

Answer

Ehlers-Danlos syndrome

Answer

Werner syndrome

Answer

Laurence-Moon-Biedl syndrome

Question 4

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

Accepted Answer

Homocystinuria

Answer

G6PD deficiency

Answer

Myotonic dystrophy

Answer

Otospongiosis

Question 5

Which of the following is an autosomal dominant metabolic disorder?

Accepted Answer

Familial hypercholesterolemia

Answer

Cystic fibrosis

Answer

Phenylketonuria

Answer

Alpha-1 antitrypsin deficiency

Question 6

Edwards syndrome is associated with which chromosomal abnormality?

Accepted Answer

Trisomy 18

Answer

Trisomy 21

Answer

Trisomy 13

Answer

5p deletion

Question 7

Adrenomyeloneuropathy, a variant of adrenoleukodystrophy which manifests as adrenal insufficiency beginning in childhood and later develops into a progressive spastic paraparesis, is transmitted as:

Accepted Answer

X-linked disorder

Answer

Autosomal dominant

Answer

Autosomal recessive

Answer

Sporadic

Question 8

Fredrich's ataxia is caused by which type of mutation?

Accepted Answer

Expanded trinucleotide repeat

Answer

Point mutation

Answer

Missense mutation

Answer

Inversion

Question 9

Non-frameshift mutation of the dystrophin gene causes which of the following conditions?

Accepted Answer

Becker's Muscular Dystrophy

Answer

Duchenne Muscular Dystrophy

Answer

Myotonic Dystrophy

Answer

Limb Girdle Dystrophy

Question 10

Classic form of Alport syndrome is inherited as:

Accepted Answer

X-linked

Answer

Autosomal recessive

Answer

Autosomal dominant

Answer

Sporadic

Genetics and Disease — MCQs

Genetics and Disease — MCQs

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