Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere

Lemmers, Richard J.L.F.; Kievit, Peggy de; Sandkuijl, Lodewijk A.; Padberg, George W.; Ommen, Gert‐Jan B. van; Frants, Rune R.; Maarel, Silvère M. van der

doi:10.1038/ng999

Cited by 257 publications

(235 citation statements)

References 12 publications

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“…All patients had previously undergone DNA diagnostic testing for FSHD1, and all but one had been identified as carrying 411 4q35-located D4Z4 repeats, as determined by p13E11 hybridisation to EcoRI-digested and EcoRI/BlnI-digested genomic DNA. 13,14 The 4qA-defined and 4qB-defined subtelomeric alleles were also identified as previously reported. 13,14 4q35.2-associated haplotypes were assessed as previously reported.…”

Section: Methodssupporting

confidence: 67%

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Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy

Winston¹,

Duerden²,

Mort³

et al. 2014

Eur J Hum Genet

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Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4 chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical severity is inversely related to the number of repeats. In contrast, FSHD2 patients also have inappropriate expression of DUX4 in skeletal muscle, but due to constitutional mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which cause global hypomethylation and hence general relaxation of chromatin. Thirty patients originally referred for FSHD testing were screened for SMCHD1 mutations. Twenty-nine had 411 D4Z4 repeats. SMCHD1 c.1040 þ 1G4A, a pathogenic splice-site variant, was identified in a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable phenotype (in which a LMNA1 sequence variant was previously described), and SMCHD1 c.2606 G4T, a putative missense variant (p.Gly869Val) with strong in vitro indications of pathogenicity, was identified in a family with an unusual muscular dystrophy with some FSHD-like features. The two families described here emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider role in global genomic methylation, the possibility exists that it could be involved in other complex undiagnosed muscle disorders. Thus far, only 15 constitutional mutations have been identified in SMCHD1, and these two sequence variants add to the molecular and phenotypic spectrum associated with FSHD.

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Section: Methodssupporting

confidence: 67%

“…13,14 The 4qA-defined and 4qB-defined subtelomeric alleles were also identified as previously reported. 13,14 4q35.2-associated haplotypes were assessed as previously reported. 15,16 D4Z4 methylation analysis Methylation-sensitive restriction digestion.…”

Section: Methodssupporting

confidence: 67%

Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy

Winston¹,

Duerden²,

Mort³

et al. 2014

Eur J Hum Genet

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“…All individuals included in this study were analyzed previously for their allele size, constitution of repeats arrays on chromosomes 4q and 10q and haplotypes after informed consent was obtained [17,18] . In total, DNA of 70 control individuals, both family members and unrelated individuals (16 monosomic, 40 disomic and 14 trisomic), and DNA of 54 FSHD1 patients with a D4Z4 contraction (10 monosomic, 29 disomic and 15 trisomic) were analyzed.…”

Section: Patients and Controlsmentioning

confidence: 99%

“…The 4qA161 haplotype is the most prevalent A haplotype in the Caucasian population and can be observed in ~39% of control individuals [17] . Thus far, only contractions in the 4qA161 haplotype have been shown to cause FSHD, while contractions in other 4q haplotypes such as 4qA166 and 4qB163 are non-pathogenic [17][18][19] ). Therefore, it is hypothesized that haplotype-specific sequence polymorphisms are mechanistically linked to FSHD pathogenesis [17] .…”

Section: Introductionmentioning

confidence: 99%

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

et al. 2009

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Facioscapulohumeral muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation. To date however, the methylation status of contracted repeats on non-pathogenic haplotypes has not been studied. We have performed a detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We show that patients with a D4Z4 deletion (FSHD1) have D4Z4-restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a non-pathogenic chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In fifteen FSHD families without D4Z4 contractions but with at least one 4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD; (1) contraction-dependent or (2) contraction-independent D4Z4 hypomethylation on the 4qA161 subtelomere.

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“…[10][11][12] To cause FSHD, D4Z4 chromatin relaxation must occur on a specific genetic background of chromosome 4 (most often 4A161) that facilitates the production of stable DUX4 mRNA due to the presence of a polymorphic DUX4 polyadenylation signal distal to the D4Z4 repeat array. 8,13 D4Z4 chromatin relaxation on non-permissive chromosomes lacking a DUX4 polyadenylation signal do not cause FSHD in the absence of detectable levels of DUX4 mRNA. 8,14 Autosomal dominant FSHD1 is the most common form of FSHD (495%), in which D4Z4 chromatin relaxation and DUX4 expression are caused by a contraction of the D4Z4 repeat array to a size of 1-10 units.…”

Section: Introductionmentioning

confidence: 91%

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

et al. 2015

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Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 functionaffecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having two SMCHD1 missense variants that affect function is compatible with life in males and females, which is remarkable considering its role in X inactivation in mice. The study also highlights the variability in SMCHD1 variants underlying FSHD2 and the predictive value of D4Z4 methylation analysis in determining the functional consequences of SMCHD1 variants of unknown significance.

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Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere

Cited by 257 publications

References 12 publications

Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy

Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy

Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD

Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

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