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Facioscapulohumeral Muscular Dystrophy — SCE Neurology MCQ

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HardPeripheral Neuropathy & NeuromuscularFacioscapulohumeral Muscular DystrophySCE Neurology

A patient has a typical facioscapulohumeral muscular dystrophy phenotype. Molecular testing identifies several abnormalities. Which result specifically establishes FSHD1 rather than FSHD2 or a non-pathogenic D4Z4 contraction?

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Correct answer: A — A pathogenic D4Z4 contraction at 4q35 on a permissive chromosome 4 haplotype

FSHD1 requires a heterozygous pathogenic contraction of the D4Z4 repeat array at 4q35 together with a permissive chromosome 4 haplotype because that configuration permits stable DUX4 expression. A contraction on a non-permissive haplotype is not sufficient. FSHD2 usually combines D4Z4 hypomethylation with a permissive haplotype and a pathogenic variant in a chromatin regulator such as SMCHD1. DUX4 expression or hypomethylation without the defining chromosome configuration does not by itself establish FSHD1.

Reference: GeneReviews: Facioscapulohumeral Muscular Dystrophy. https://www.ncbi.nlm.nih.gov/sites/books/NBK1443/