USMLE Step 1 Question (Genetics)

Genetics/Biochemistry/Cell Biology

The following is a high-yield USMLE Step 1 question that will test your understanding of genetics, biochemistry, and cellular biology.

It is followed by a deep dive into each answer choice—the answer can be found at the bottom of the post.

Good luck!

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QUESTION:

A 23-year-old female with a history of joint hypermobility and easy bruising presents to her primary care physician for a routine follow-up visit. She reports occasional palpitations and shortness of breath. Her vital signs include temperature 98.6°F (37°C), pulse 80/minute, respirations 18/minute, blood pressure 110/70 mmHg, and oxygen saturation 98% on room air. Physical examination shows hypermobile joints and a mid-systolic click followed by a late systolic murmur best heard at the heart’s apex. Considering the patient's clinical presentation, which of the following is the most likely underlying cause of her auscultatory findings?

A. Deficiency of elastin in the mitral valve leaflets

B. Abnormal cross-linking of collagen fibers

C. Mutation in fibrillin-1 gene

D. Deficiency of vitamin C

E. Accumulation of glycosaminoglycans

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To see the answer, scroll to the end of the post. If you’re unsure, check out the DEEP DIVE into each answer choice below.

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DEEP DIVE:

This question presents a case of a young female with a history of joint hypermobility, easy bruising, occasional palpitations, and shortness of breath. The physical examination reveals hyperextensible joints and a mid-systolic click followed by a late systolic murmur, which is consistent with mitral valve prolapse (MVP). Based on her clinical presentation, the question asks for the most likely underlying cause of her MVP. As you contemplate this question, be sure to consider the patient's age, gender, medical history, and physical examination findings to diagnose her condition correctly.

This is a 2nd-order question:

1st: Make a diagnosis based on the given information

2nd: Identify the underlying cause of the diagnosis

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A. Mutation in the elastin gene

Elastin is an essential component of connective tissues, providing elasticity and resilience. A deficiency in elastin can lead to weakened and redundant valve leaflets, potentially causing MVP. However, elastin deficiency is more commonly associated with other connective tissue disorders, such as Williams syndrome, supravalvular aortic stenosis, and cutis laxa.

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B. Abnormal cross-linking of collagen fibers

Collagen is the main structural protein in connective tissues, providing strength and support. Abnormal cross-linking of collagen fibers can result in weakened and less resilient tissues, which may contribute to MVP. This abnormality is often seen in conditions like Ehlers-Danlos syndrome (EDS), particularly the classical and hypermobile types. However, the absence of skin striae in the patient's presentation makes this choice less likely.

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C. Mutation in fibrillin-1 gene

Fibrillin-1 is a glycoprotein that plays a crucial role in forming and maintaining elastic fibers. Mutations in the fibrillin-1 gene are the primary cause of Marfan syndrome, an autosomal dominant connective tissue disorder characterized by tall stature, long limbs, joint hypermobility, and cardiovascular manifestations, including MVP and aortic root dilation.

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D. Deficiency of vitamin C

Vitamin C is essential for the synthesis and maintenance of collagen. A deficiency in vitamin C can lead to impaired collagen production and weakened connective tissues, as seen in scurvy. However, vitamin C deficiency is rare in developed countries and is not typically associated with MVP or the presence of striae.

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E. Accumulation of glycosaminoglycans

Glycosaminoglycans (GAGs) are long, unbranched polysaccharides that are a major component of the extracellular matrix in connective tissues. An accumulation of GAGs can lead to thickened and dysplastic valve leaflets, as seen in mucopolysaccharidoses (MPS). However, MPSs are typically associated with more severe and multi-systemic manifestations, such as skeletal abnormalities, coarse facial features, and cognitive impairment, all of which are not seen in this patient.

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THE VERDICT: The patient's history of joint hypermobility, easy bruising, and the presence of mitral valve prolapse suggests an underlying connective tissue disorder. Without dermatological findings, which are more commonly associated with Ehlers-Danlos syndrome (EDS), Marfan syndrome becomes the most likely diagnosis.

A mutation in the fibrillin-1 gene leads to defects in the formation and maintenance of elastic fibers, resulting in joint hypermobility, cardiovascular manifestations (including MVP), and an increased risk of bruising due to weakened connective tissues.

The mid-systolic click followed by a late systolic murmur heard on auscultation is a classic finding in MVP. Although other connective tissue disorders, such as EDS, can also present with joint hypermobility and MVP, the patient's specific constellation of findings, particularly the absence of hyperextensible skin and/or striae, is more consistent with Marfan syndrome.

FINAL ANSWER: C. Mutation in fibrillin-1 gene

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