title: Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome.
abstract: 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.
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Richard J L F
authors.initials: RJ
authors.lastname: Lemmers
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Marlinde L
authors.initials: ML
authors.lastname: van den Boogaard
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: van der Vliet
authors.affiliation: Neuromuscular Disease Unit, Department of Neurology, University of Rochester Medical Center, Rochester, New York.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Donlin-Smith
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Sharon P
authors.initials: SP
authors.lastname: Nations
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Claudia A L
authors.initials: CA
authors.lastname: Ruivenkamp
authors.affiliation: University of Texas Health Science Center at San Antonio, Chromosome 18 Research Center, San Antonio, Texas.
authors.forename: Patricia
authors.initials: P
authors.lastname: Heard
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Bakker
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tapscott
authors.affiliation: University of Texas Health Science Center at San Antonio, Chromosome 18 Research Center, San Antonio, Texas.
authors.forename: Jannine D
authors.initials: JD
authors.lastname: Cody
authors.affiliation: Neuromuscular Disease Unit, Department of Neurology, University of Rochester Medical Center, Rochester, New York.
authors.forename: Rabi
authors.initials: R
authors.lastname: Tawil
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D000328:Adult; D000368:Aged; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D055106:Genome-Wide Association Study; D057898:Hemizygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics*; D010375:Pedigree
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C578241:SMCHD1 protein, human
keywords: D4Z4; FSHD; SMCHD1; epiallele; epigenetic modifier
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