Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2

Satomi Mitsuhashi, Steven E. Boyden, Elicia A. Estrella, Takako I. Jones, Fedik Rahimov, Timothy W. Yu, Basil T. Darras, Anthony A. Amato, Rebecca D. Folkerth, Peter L. Jones, Louis M. Kunkel, Peter B. Kang

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31 Scopus citations


FSHD2 is a rare form of facioscapulohumeral muscular dystrophy (FSHD) characterized by the absence of a contraction in the D4Z4 macrosatellite repeat region on chromosome 4q35 that is the hallmark of FSHD1. However, hypomethylation of this region is common to both subtypes. Recently, mutations in SMCHD1 combined with a permissive 4q35 allele were reported to cause FSHD2. We identified a novel p.Lys275del SMCHD1 mutation in a family affected with FSHD2 using whole-exome sequencing and linkage analysis. This mutation alters a highly conserved amino acid in the ATPase domain of SMCHD1. Subject III-11 is a male who developed asymmetrical muscle weakness characteristic of FSHD at 13. years. Physical examination revealed marked bilateral atrophy at biceps brachii, bilateral scapular winging, some asymmetrical weakness at tibialis anterior and peroneal muscles, and mild lower facial weakness. Biopsy of biceps brachii in subject II-5, the father of III-11, demonstrated lobulated fibers and dystrophic changes. Endomysial and perivascular inflammation was found, which has been reported in FSHD1 but not FSHD2. Given the previous report of SMCHD1 mutations in FSHD2 and the clinical presentations consistent with the FSHD phenotype, we conclude that the SMCHD1 mutation is the likely cause of the disease in this family.

Original languageEnglish (US)
Pages (from-to)975-980
Number of pages6
JournalNeuromuscular Disorders
Issue number12
StatePublished - Dec 2013
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank Catherine Brownstein, David Margulies, the staff of the Genetic Diagnostic Laboratory and the entire Interpretive Genomic Services team at Boston Children’s Hospital for facilitating sample analysis. This study was supported by the William Randolph Hearst Fund at Harvard Medical School (S.M.), Muscular Dystrophy Association (MDA) Research Grant 186796 (P.B.K.), NIH R01 NS080929 (P.B.K.), the Association Française contre les Myopathies Grant 15700 (T.I.J., P.L.J.), Muscular Dystrophy Association (MDA) Development Grant 202863 (F.R.), and the Bernard F. and Alva B. Gimbel Foundation (L.M.K.). Microarray genotyping and Sanger DNA sequencing experiments were performed in the Molecular Genetics Core Facility at Boston Children’s Hospital, supported by NIH P30 HD18655 through the Intellectual and Developmental Disabilities Research Center and NIH P50NS40828 through the Neuromuscular Disease Project.


  • DUX4
  • Facioscapulohumeral muscular dystrophy 2
  • SMCHD1


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