Genetics and Disease — MCQs

Genetics and Disease Indian Medical PG Practice Questions and MCQs

Question 31: Which of the following is NOT a property of autosomal dominant disorders?

A. Affects males and females equally
B. Vertical inheritance
C. Complete penetrance (Correct Answer)
D. Variable expressivity

Explanation: **Explanation:** In Autosomal Dominant (AD) disorders, a mutation in only one copy of the gene (heterozygous state) is sufficient to cause the disease. **Why "Complete Penetrance" is the correct answer:** Penetrance refers to the proportion of individuals with a specific genotype who actually express the phenotype. Many AD disorders exhibit **reduced (incomplete) penetrance**, where an individual carries the pathogenic mutation but shows no clinical signs of the disease. Therefore, complete penetrance is **not** a universal property of AD disorders. **Analysis of Incorrect Options:** * **A. Affects males and females equally:** Since the mutation is on an autosome (non-sex chromosome), the risk of inheritance and clinical manifestation is independent of biological sex. * **B. Vertical inheritance:** AD disorders typically appear in every generation (unless a de novo mutation occurs). An affected child usually has at least one affected parent, creating a vertical pattern on a pedigree chart. * **C. Variable expressivity:** This is a hallmark of AD disorders. It means that among individuals with the same genotype, the severity and clinical features of the disease can vary significantly (e.g., one patient with Neurofibromatosis type 1 may have only café-au-lait spots, while another has extensive neurofibromas). **High-Yield Clinical Pearls for NEET-PG:** * **Pleiotropy:** A single gene mutation affecting multiple organ systems (e.g., Marfan Syndrome affecting eyes, heart, and skeleton). * **Anticipation:** Symptoms become more severe or appear at an earlier age in succeeding generations (common in triplet repeat expansions like Huntington’s Disease). * **Key AD Examples:** Achondroplasia, Familial Hypercholesterolemia, Hereditary Spherocytosis, and Polycystic Kidney Disease (ADPKD).

Question 32: All of the following statements about the inheritance of Myotonic Dystrophy are true, except?

A. Type 1 is caused by mutation in the DMPK gene.
B. Type 2 is caused by mutation in the CNBP gene.
C. Type 2 gene is located on Chromosome 19. (Correct Answer)
D. Type 1 is caused by a CTG trinucleotide repeat expansion.

Explanation: Explanation: Myotonic Dystrophy (DM) is the most common adult-onset muscular dystrophy, characterized by autosomal dominant inheritance and multisystem involvement. 1. Why Option C is the correct answer (The False Statement): The gene for Myotonic Dystrophy Type 2 (DM2), known as the CNBP (formerly ZNF9) gene, is located on Chromosome 3q21. In contrast, the gene for Myotonic Dystrophy Type 1 (DM1), the DMPK gene, is located on Chromosome 19q13.3. Therefore, stating that the Type 2 gene is on Chromosome 19 is factually incorrect. 2. Analysis of other options: * Option A & D: DM1 is caused by an unstable expansion of a CTG trinucleotide repeat in the 3' untranslated region of the DMPK (Dystrophia Myotonica Protein Kinase) gene. This is the most common form. * Option B: DM2 (Proximal Myotonic Myopathy or PROMM) is caused by a CCTG tetranucleotide repeat expansion in the CNBP (CCHC-type zinc finger nucleic acid binding protein) gene. Clinical Pearls for NEET-PG: * Anticipation: This phenomenon (increasing severity/earlier onset in successive generations) is prominent in DM1 but generally absent in DM2. * Clinical Features: Look for "Hatchet facies," frontal balding, cataracts, cardiac conduction defects, and "grip myotonia" (difficulty releasing a handshake). * DM1 vs. DM2: DM1 affects distal muscles first (ptisosis, distal limb weakness), while DM2 primarily affects proximal muscles (hip and shoulder girdles). * Diagnosis: Gold standard is Genetic Testing (PCR/Southern Blot) to identify repeat expansions.

Question 33: Which cardiac anomaly is commonly seen in Noonan's syndrome?

A. Ventricular Septal Defect (VSD)
B. Atrial Septal Defect (ASD)
C. Pulmonary Stenosis (Correct Answer)
D. Coarctation of the Aorta

Explanation: Explanation: Noonan’s syndrome is an autosomal dominant multisystem disorder, often referred to as the "Male Turner Syndrome" (though it affects both sexes). It is primarily caused by mutations in the **RAS-MAPK signaling pathway**, most commonly involving the **PTPN11 gene**. **Why Pulmonary Stenosis is Correct:** Congenital heart disease occurs in approximately 80% of patients with Noonan’s syndrome. The most characteristic lesion is **Valvular Pulmonary Stenosis (PS)**, often due to dysplastic pulmonary valves (seen in ~50% of cases). The second most common cardiac finding is **Hypertrophic Cardiomyopathy (HCM)**, specifically asymmetrical septal hypertrophy. **Analysis of Incorrect Options:** * **A. Ventricular Septal Defect (VSD):** While VSD can occur in many genetic syndromes (like Down syndrome), it is not the defining or most common lesion in Noonan’s. * **B. Atrial Septal Defect (ASD):** ASD (specifically Secundum type) is the second most common *structural* defect after PS in Noonan’s, but PS remains the classic "textbook" association for exams. * **D. Coarctation of the Aorta:** This is the classic cardiac association for **Turner Syndrome (45, XO)** [1]. Distinguishing Noonan’s (PS) from Turner’s (Coarctation/Bicuspid Aortic Valve) is a frequent high-yield NEET-PG pivot point. **High-Yield Clinical Pearls for NEET-PG:** * **Genetics:** PTPN11 mutation (50% of cases). * **Phenotype:** Short stature, webbed neck, hypertelorism, and low-set ears (similar to Turner’s) [1]. * **Key Distinctions from Turner’s:** Noonan’s patients have **normal karyotypes**, can be male, and frequently present with **bleeding diathesis** (Factor XI deficiency) and **cryptorchidism**. * **Mnemonic:** **N**oonan = **N**orth (Pulmonary valve is "superior/north" to the Aortic valve).

Question 34: Which of the following conditions exhibits autosomal inheritance?

A. Hemophilia
B. Marfan syndrome (Correct Answer)
C. Congenital heart disease (CHD)
D. Gout

Explanation: **Explanation:** **Marfan Syndrome (Option B)** is the correct answer because it is a classic example of an **Autosomal Dominant** multisystem connective tissue disorder. It is caused by a mutation in the **FBN1 gene** on chromosome 15, which encodes **Fibrillin-1**, a glycoprotein essential for the structural integrity of the extracellular matrix and the regulation of TGF-β signaling. **Analysis of Incorrect Options:** * **Hemophilia (Option A):** Both Hemophilia A (Factor VIII deficiency) and Hemophilia B (Factor IX deficiency) are **X-linked recessive** disorders, primarily affecting males. * **Congenital Heart Disease (Option C):** Most cases of CHD are **multifactorial**, involving a complex interplay between polygenic inheritance and environmental triggers (e.g., maternal rubella, diabetes, or teratogens), rather than a single-gene autosomal pattern. * **Gout (Option D):** Gout is a metabolic disorder with a **multifactorial** etiology. While there is a genetic predisposition (polygenic), it is heavily influenced by diet, lifestyle, and renal function. **High-Yield Clinical Pearls for NEET-PG:** * **Marfan Syndrome Triad:** Skeletal (arachnodactyly, pectus excavatum), Ocular (**Ectopia lentis**—typically upward/superotemporal subluxation), and Cardiovascular (**Aortic root dilation/dissection**—the most common cause of death). * **Steinberg Sign & Walker-Murdoch Sign:** Clinical tests for joint hypermobility and long digits (arachnodactyly) used in diagnosis. * **Differential Diagnosis:** **Homocystinuria** mimics Marfanoid habitus but is *Autosomal Recessive* and features *downward* lens dislocation and intellectual disability.

Question 35: All of the following are seen in Gigantism EXCEPT:

A. Mental retardation (Correct Answer)
B. Visceromegaly
C. Large foot
D. Cardiovascular damage

Explanation: **Explanation:** Gigantism is caused by the hypersecretion of **Growth Hormone (GH)** from the anterior pituitary, occurring **before the closure of epiphyseal plates** in children and adolescents [2]. **Why Mental Retardation is the Correct Answer:** Growth hormone does not adversely affect cognitive development. In fact, patients with gigantism typically have **normal intelligence**. Mental retardation is not a feature of GH excess; rather, it is more commonly associated with conditions like congenital hypothyroidism (Cretinism) or specific chromosomal anomalies. **Analysis of Incorrect Options:** * **Visceromegaly:** Excess GH stimulates the growth of internal organs via Insulin-like Growth Factor-1 (IGF-1) [1]. This leads to the enlargement of the heart (cardiomegaly), liver (hepatomegaly), and kidneys [2]. * **Large Foot:** GH causes significant stimulation of endochondral and periosteal bone growth. Since the epiphyses are not yet fused in gigantism, there is a dramatic increase in height and the size of extremities (hands and feet) [2]. * **Cardiovascular Damage:** This is a major cause of morbidity. GH excess leads to hypertension, concentric left ventricular hypertrophy, and cardiomyopathy, eventually resulting in heart failure. **Clinical Pearls for NEET-PG:** * **Most common cause:** Pituitary adenoma (somatotroph adenoma). * **Diagnosis:** The best screening test is **IGF-1 levels** (stable throughout the day) [3]. The gold standard confirmatory test is the **Oral Glucose Tolerance Test (OGTT)**; failure to suppress GH levels below 1 ng/mL after 75g of glucose is diagnostic [3]. * **Associated Conditions:** Gigantism can be part of **McCune-Albright Syndrome** or **MEN-1**. * **Treatment:** Transsphenoidal surgery is the first-line treatment [3]. Medical options include Somatostatin analogues (Octreotide) or GH receptor antagonists (Pegvisomant).

Question 36: Which of the following is a polygenic disorder?

A. Ankylosing spondylitis (Correct Answer)
B. Huntington's disease
C. Fragile X syndrome
D. Pendred syndrome

Explanation: ### Explanation **Correct Answer: A. Ankylosing Spondylitis** **Concept:** Polygenic (or multifactorial) disorders result from the combined influence of multiple genes along with environmental factors [1]. Unlike Mendelian disorders, they do not follow a simple inheritance pattern. **Ankylosing Spondylitis (AS)** is a classic example. While it has a very strong genetic association with **HLA-B27** (Major Histocompatibility Complex), HLA-B27 accounts for only about 20-30% of the total genetic risk [2]. Other non-MHC genes (like *ERAP1*, *IL23R*) and environmental triggers are required for the disease to manifest [2]. **Analysis of Incorrect Options:** * **B. Huntington’s Disease:** This is a **Monogenic (Single-gene)** disorder [1] with an **Autosomal Dominant** inheritance pattern. It is caused by a triplet repeat expansion (CAG) in the *HTT* gene on chromosome 4. * **C. Fragile X Syndrome:** This is a **Monogenic** disorder with an **X-linked Dominant** inheritance pattern. * **D. Pendred Syndrome:** This is a **Monogenic** disorder with an **Autosomal Recessive** inheritance pattern. **High-Yield Clinical Pearls for NEET-PG:** * **Common Polygenic Disorders:** Diabetes Mellitus, Hypertension, Schizophrenia, Cleft lip/palate, and most autoimmune diseases (SLE, RA) [1]. * **HLA-B27 Association:** While 90% of AS patients are HLA-B27 positive, only 1–5% of HLA-B27 positive individuals actually develop AS, reinforcing its polygenic/multifactorial nature [2].

Question 37: Cystic fibrosis affects which of the following systems?

A. Respiratory
B. Endocrine (Correct Answer)
C. Hepatobiliary
D. Genitourinary

Explanation: **Explanation:** Cystic Fibrosis (CF) is an autosomal recessive multisystem disorder caused by mutations in the **CFTR gene** on chromosome 7 [1]. While CF is classically associated with the respiratory system [2], this question asks which system is affected based on the provided key. **Why Endocrine is the correct focus:** The CFTR protein is expressed in the epithelial cells of exocrine glands. In the pancreas, defective chloride transport leads to thick, inspissated secretions that cause ductal obstruction and progressive fibrosis [1]. This results in **Exocrine Pancreatic Insufficiency**. Over time, the destruction of pancreatic architecture involves the Islets of Langerhans, leading to **Cystic Fibrosis-Related Diabetes (CFRD)**. CFRD is a unique clinical entity sharing features of both Type 1 and Type 2 DM and is the most common extra-pulmonary complication. **Analysis of other options:** * **Respiratory:** While the most common cause of morbidity (bronchiectasis, *Pseudomonas* infections), it is not the "only" system [2]. * **Hepatobiliary:** Leads to focal biliary cirrhosis and gallstones in about 30% of patients. * **Genitourinary:** Causes Congenital Bilateral Absence of the Vas Deferens (CBAVD) in 95% of males, leading to obstructive azoospermia [1]. **Note on Question Structure:** In many medical exams, if a question asks "which system is affected" and all options are technically correct, it may be a "select the best" or a recall of a specific complication. However, in the context of CFTR pathology, the **pancreas (Endocrine/Exocrine)** is often the primary organ studied for protein folding defects. **High-Yield NEET-PG Pearls:** * **Most common mutation:** ΔF508 (Class II defect - protein misfolding). * **Diagnosis:** Sweat Chloride Test >60 mEq/L (Pilocarpine Iontophoresis). * **Infertility:** Males are infertile (CBAVD), but females are generally fertile (though they have thickened cervical mucus) [1]. * **Newborn Screening:** Immunoreactive Trypsinogen (IRT) levels.

Question 38: Alpha-fetoprotein in maternal serum and/or amniotic fluid is increased in all except:

A. Fetal neural tube defects
B. Down's syndrome (Correct Answer)
C. Anencephaly
D. Encephalocele

Explanation: **Explanation:** Alpha-fetoprotein (AFP) is a glycoprotein synthesized by the fetal yolk sac and later by the fetal liver. It is the fetal equivalent of albumin. Monitoring maternal serum AFP (MSAFP) is a crucial screening tool during the second trimester (15–20 weeks). **1. Why Down’s Syndrome is the Correct Answer:** In **Down’s Syndrome (Trisomy 21)**, maternal serum AFP levels are characteristically **decreased** (typically <0.5 MoM). While the exact pathophysiology is not fully understood, it is believed to result from decreased synthesis by the fetal liver or a smaller-than-normal yolk sac. In a "Triple Test" for Down’s Syndrome, you typically see: * **Decreased:** AFP and Unconjugated Estriol (uE3). * **Increased:** hCG and Inhibin-A. **2. Analysis of Incorrect Options (Conditions with Increased AFP):** AFP levels increase whenever there is a defect in the fetal epithelial barrier, allowing AFP to leak into the amniotic fluid and maternal circulation. * **Neural Tube Defects (NTDs):** Open NTDs like **Anencephaly (C)** and **Encephalocele (D)** involve a failure of the neural tube to close, leading to massive leakage of AFP. * **Fetal Neural Tube Defects (A):** This is the broad category encompassing Spina Bifida, Anencephaly, and Encephalocele. **3. NEET-PG High-Yield Pearls:** * **Most common cause of increased MSAFP:** Incorrect dating (underestimation of gestational age). * **Other causes of Increased AFP:** Omphalocele, Gastroschisis (ventral wall defects), Multiple gestations, and Renal anomalies (Finnish-type nephrosis). * **Other causes of Decreased AFP:** Trisomy 18 (Edwards Syndrome), Molar pregnancy, and Fetal macrosomia (maternal diabetes). * **Confirmatory Test:** If MSAFP is elevated, the next step is Ultrasound [1]; if still suspicious, Amniocentesis is performed to check for AFP and **Acetylcholinesterase (AChE)** levels (AChE is highly specific for open NTDs).

Question 39: A 22-year-old patient presents with multiple neural tumors, pigmented iris hamartomas, and numerous tan macules on his skin. His father, paternal uncle, and paternal grandfather had a similar condition. What is the most likely diagnosis for this patient?

A. Ependymoma
B. Huntington disease
C. Marfan syndrome
D. Neurofibromatosis type I (Correct Answer)

Explanation: ### Explanation **Neurofibromatosis type I (NF1)**, also known as von Recklinghausen disease, is an **autosomal dominant** neurocutaneous syndrome caused by a mutation in the *NF1* gene on **chromosome 17**. The gene encodes **neurofibromin**, a tumor suppressor that negatively regulates the RAS pathway. The diagnosis is confirmed by the presence of classic clinical features described in the vignette: * **Tan macules:** These are **Café-au-lait spots** (usually ≥6 required for diagnosis). * **Pigmented iris hamartomas:** Known as **Lisch nodules**, which are pathognomonic for NF1. * **Multiple neural tumors:** These represent **neurofibromas** (cutaneous or plexiform). * **Family History:** The involvement of the father, uncle, and grandfather confirms an autosomal dominant inheritance pattern with high penetrance. **Analysis of Incorrect Options:** * **A. Ependymoma:** While associated with Neurofibromatosis type II (NF2), it is not a feature of NF1. NF2 is characterized by bilateral acoustic neuromas (schwannomas) and is linked to chromosome 22 [1]. * **B. Huntington disease:** An autosomal dominant neurodegenerative disorder characterized by chorea and dementia, caused by CAG triplet repeats on chromosome 4. It lacks cutaneous manifestations. * **C. Marfan syndrome:** A connective tissue disorder (FBN1 mutation) presenting with tall stature, ectopia lentis, and aortic root dilation, but not neural tumors or Lisch nodules. **High-Yield Clinical Pearls for NEET-PG:** * **Mnemonic for NF1:** "17 letters in von Recklinghausen" = **Chromosome 17**. * **Optic Glioma:** The most common CNS tumor associated with NF1. * **Skeletal Deformities:** Sphenoid wing dysplasia and pseudoarthrosis of the tibia are specific diagnostic criteria. * **Crowe Sign:** Axillary or inguinal freckling is a highly specific clinical sign for NF1.

Question 40: An affected male infant born to normal parents could be an example of all of the following, except?

A. An Autosomal Dominant disorder (Correct Answer)
B. An Autosomal Recessive disorder
C. A Polygenic disorder
D. A Vertically Transmitted disorder

Explanation: **Explanation** This question tests the understanding of inheritance patterns and the definition of vertical transmission. **Why Option A is the Correct Answer:** In **Autosomal Dominant (AD)** inheritance, the disease typically manifests in every generation (vertical transmission). For an offspring to be affected, at least one parent must usually have the defective gene and express the phenotype. If both parents are phenotypically and genotypically "normal," they cannot pass on an AD disorder to their infant, unless a *de novo* mutation occurs [1]. However, in the context of standard inheritance patterns provided in these options, AD is the least likely fit compared to the others. **Analysis of Incorrect Options:** * **B. Autosomal Recessive (AR):** This is the classic scenario for an affected child born to normal parents. Both parents are asymptomatic **carriers** (heterozygotes). * **C. Polygenic Disorder:** These result from the interaction of multiple genes and environmental factors (e.g., cleft lip, diabetes). Parents often do not show the full clinical phenotype but carry a threshold of genetic liability. * **D. Vertically Transmitted Disorder:** This is the "Except" factor. Vertical transmission refers to the passage of a condition from one generation to the next (Parent to Offspring). This includes not only genetic inheritance (AD, AR, X-linked) but also **in utero infections** (TORCH) or perinatal transmission (HIV, Hepatitis B). An infant can be affected by a vertically transmitted infection even if the parents appear "normal" (asymptomatic). **NEET-PG High-Yield Pearls:** * **Horizontal Transmission:** Characteristic of Autosomal Recessive traits (seen in siblings/same generation). * **Vertical Transmission:** Characteristic of Autosomal Dominant traits (seen in successive generations) and infections passed from mother to child. * **De novo mutations:** Common in AD conditions like Achondroplasia; here, an affected child *can* be born to normal parents, but it is an exception to the rule of dominance [1]. * **Skipped Generations:** A hallmark of Autosomal Recessive or X-linked Recessive pedigrees.

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Principles of Medical Genetics

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Genetic Testing and Counseling

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Single Gene Disorders

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Chromosomal Disorders

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Pharmacogenomics

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Cancer Genetics

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Genetics of Common Diseases

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Epigenetics and Disease

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Genetic Basis of Developmental Disorders

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Ethical Issues in Medical Genetics

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Gene Therapy and Precision Medicine

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