A 22-year-old tall male presents with long limbs, increased arm span, hypermobile joints, and high-arched palate. On examination, he has lens subluxation and a diastolic murmur suggestive of aortic root dilation. Which of the following genes is most likely mutated in this condition?

Explanation

## Correct Answer: C. Fibrillin-1 (FBN1) This clinical presentation is pathognomonic for **Marfan syndrome**, an autosomal dominant connective tissue disorder caused by mutations in the **FBN1 gene** on chromosome 15q21. Fibrillin-1 is a crucial component of extracellular microfibrils that serve as scaffolding for elastic fiber assembly and as a reservoir for TGF-β signaling. The constellation of skeletal features (tall stature, long limbs, increased arm span-to-height ratio >1.05, arachnodactyly, hypermobile joints, high-arched palate), ocular manifestations (lens subluxation/ectopia lentis, typically superotemporal), and cardiovascular complications (aortic root dilation with aortic regurgitation causing diastolic murmur) are classic hallmarks. FBN1 mutations disrupt microfibril integrity, leading to weakened connective tissue throughout the body. The aortic root dilation is the most life-threatening complication, predisposing to aortic dissection—a leading cause of premature death in Marfan patients. Indian epidemiology shows Marfan syndrome in approximately 1 in 5,000 live births. Diagnosis is clinical (revised Ghent nosology) with genetic confirmation via FBN1 sequencing. Management includes beta-blockers or ARBs (losartan preferred in India) to slow aortic dilation, ophthalmologic screening, and genetic counseling. ## Why the other options are wrong **A. COL1A1** — COL1A1 mutations cause **Osteogenesis Imperfecta (OI)**, not Marfan syndrome. OI presents with brittle bones, recurrent fractures, blue sclerae, and hearing loss—not the skeletal overgrowth, lens subluxation, or aortic dilation seen here. This is an NBE trap pairing collagen genes with connective tissue disorders; students may confuse OI with Marfan if they only remember 'collagen defect.' **B. Elastin** — Elastin gene mutations cause **Williams syndrome** (supravalvular aortic stenosis, not dilation) and **Cutis laxa** (loose, redundant skin). Neither presents with the tall stature, arachnodactyly, lens ectopia, or aortic root dilation characteristic of Marfan syndrome. Elastin defects produce elastic fiber fragmentation but lack the systemic skeletal and ocular features. **D. COL4A5** — COL4A5 mutations cause **X-linked Alport syndrome**, characterized by progressive glomerulonephritis, sensorineural hearing loss, and ocular abnormalities (anterior lenticonus, not subluxation). Males present with hematuria and renal failure, not tall stature, arachnodactyly, or aortic dilation. This trap exploits confusion between different collagen-related syndromes. ## High-Yield Facts - **FBN1 mutations** cause Marfan syndrome via defective microfibril assembly and impaired TGF-β sequestration. - **Lens subluxation** (superotemporal ectopia) is the pathognomonic ocular sign of Marfan syndrome; occurs in ~60% of patients. - **Aortic root dilation** is the most life-threatening complication; prophylactic beta-blockers or losartan reduce dissection risk by ~50% in Indian cohorts. - **Arm span-to-height ratio >1.05** and **positive thumb sign** (thumb extends beyond palm when fist is clenched) are screening skeletal markers. - Marfan syndrome follows **autosomal dominant inheritance** with ~25% new mutations; genetic counseling mandatory for family screening in Indian families. ## Mnemonics **MARFAN Skeletal-Ocular-Cardiac Triad** **M**icrofibril defect (FBN1) → **A**rachnodactyly + tall stature, **R**oot dilation (aortic), **F**ibrillin-1 gene, **A**ortic regurgitation (diastolic murmur), **N**ormal intelligence. Lens **E**ctopia (superotemporal), **C**ardiac dissection risk. **Connective Tissue Disorder Gene Pairing** **Marfan = Fibrillin-1 (FBN1)**, Ehlers-Danlos = COL3A1/COL1A1, Osteogenesis Imperfecta = COL1A1, Alport = COL4A5. Use: rapid differential when given a gene name. ## NBE Trap NBE pairs **COL1A1 (OI) with connective tissue skeletal features** to trap students who remember "collagen defects cause tall/skeletal problems" without distinguishing OI's fracture phenotype from Marfan's overgrowth phenotype. The presence of aortic dilation and lens subluxation are the discriminators that exclude collagen genes. ## Clinical Pearl In Indian clinical practice, Marfan syndrome is often diagnosed late because tall stature is normalized in some populations. The **combination of lens ectopia + aortic root dilation on echocardiography** is the diagnostic red flag that should trigger FBN1 testing and immediate cardiology referral to prevent sudden cardiac death—a leading cause of mortality in undiagnosed Indian Marfan patients. _Reference: Robbins & Cotran Pathologic Basis of Disease, Ch. 5 (Genetic Disorders); Harrison's Principles of Internal Medicine, Ch. 431 (Marfan Syndrome); KD Tripathi Pharmacology (ARB use in aortic dilation)_