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Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome
Author(s) -
Lemmers Richard J. L. F.,
Boogaard Marlinde L.,
Vliet Patrick J.,
DonlinSmith Colleen M.,
Nations Sharon P.,
Ruivenkamp Claudia A. L.,
Heard Patricia,
Bakker Bert,
Tapscott Stephen,
Cody Jannine D.,
Tawil Rabi,
Maarel Silvère M.
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22792
Subject(s) - facioscapulohumeral muscular dystrophy , biology , genetics , chromatin , dna methylation , muscular dystrophy , cpg site , gene , gene expression
Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4‐repeat array. The most common form, FSHD1, is caused by a D4Z4‐repeat array contraction to a size of 1–10 units (normal range 10–100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss‐of‐function mutations in the structural maintenance of chromosomes hinge domain 1 ( SMCHD1 ) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2‐Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p‐) cases have, such as these FSHD2 families, only one copy of SMCHD1 . Our finding therefore raises the possibility that 18p‐ cases are at risk of developing FSHD. To address this possibility, we combined genome‐wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p‐ and conclude that approximately 1:8 18p‐ cases might be at risk of developing FSHD.