Genetics: X-inactivation: practice question

A Anatomy question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

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Anatomy · Genetics: X-inactivation

Sample item

A 30-year-old 46,XX woman, whose mother is a carrier of Duchenne muscular dystrophy, has mild proximal weakness, calf pseudohypertrophy and raised CK. How is she symptomatic despite being heterozygous?

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

B. Skewed X-inactivation in which the normal X is mostly inactivated in muscle

Random inactivation of one X in each cell (Lyonisation) normally gives carriers a mosaic of cells, so they are usually asymptomatic. Skewed inactivation, in which most cells have the normal X inactivated, leaves mostly the mutant allele active and produces a manifesting carrier. This happens by chance, and heterozygous females are at risk of cardiomyopathy.

Option by option

  • A. A second dystrophin mutation inherited from her unaffected father

    Affected males with Duchenne rarely reproduce, so a father carrying a second mutation is not a realistic explanation.

  • B. Skewed X-inactivation in which the normal X is mostly inactivated in muscle (correct)

    Correct. Predominant activity of the mutant X leads to symptoms in a heterozygote.

  • C. Y chromosome dosage compensation failing in her cells

    Females have no Y chromosome, and dosage compensation is through X-inactivation.

  • D. Mitochondrial heteroplasmy in her muscle fibres

    The disorder is X-linked nuclear, and mitochondrial heteroplasmy does not explain it.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

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Questions about this Anatomy question

What is the answer to this Anatomy question?

The best answer is B, Skewed X-inactivation in which the normal X is mostly inactivated in muscle. Random inactivation of one X in each cell (Lyonisation) normally gives carriers a mosaic of cells, so they are usually asymptomatic.

Why is "A second dystrophin mutation inherited from her unaffected father" not the answer?

Affected males with Duchenne rarely reproduce, so a father carrying a second mutation is not a realistic explanation.

Why is "Y chromosome dosage compensation failing in her cells" not the answer?

Females have no Y chromosome, and dosage compensation is through X-inactivation.

Why is "Mitochondrial heteroplasmy in her muscle fibres" not the answer?

The disorder is X-linked nuclear, and mitochondrial heteroplasmy does not explain it.

What concept does this question test?

It tests Genetics: X-inactivation in Anatomy. Skewed inactivation, in which most cells have the normal X inactivated, leaves mostly the mutant allele active and produces a manifesting carrier. This happens by chance, and heterozygous females are at risk of cardiomyopathy.

How hard is this question?

We tag it as a multi-step question: it asks you to combine more than one idea. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study Genetics: X-inactivation?

Learn every nerve by its route, its muscles and what a lesion looks like at the bedside. That one habit answers a large share of questions. Then use the flashcards and the other Anatomy questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.