Background Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease associated with contraction of arrays of tandem 3.3-kb units (D4Z4) on subtelomeric 4q. Disease-linked arrays usually have fewer than 11 repeat units. Equally short D4Z4 arrays at subtelomeric 10q are not linked to FSHD. The newly described 4qA161 haplotype, which is more prevalent in pathogenic 4q alleles, involves sequences in and near D4Z4.
Methods We developed two new assays for 4qA161, which are based upon direct sequencing of PCR products or detecting restriction fragment length polymorphisms. They were used to analyse single nucleotide polymorphisms (SNPs) indicative of 4q161 alleles.
Results All (35/35) FSHD patients had one or two 4qA161 alleles (60% or 40%, respectively). In contrast, 46% (21/46) of control individuals had no 4qA161 allele (p<10−4), and 26% had homozygous 4qB163 alleles.
Conclusions Our results from a heterogeneous population are consistent with the previously described association of the 4qA161 haplotype with FSHD, but a causal association with pathogenesis is uncertain. In addition, we found that haplotype analysis is complicated by the presence of minor 10q alleles. Nonetheless, our sequencing assay for the 4qA161allele can enhance molecular diagnosis of FSHD, including prenatal diagnosis, and is simpler to perform than the previously described assay.
- Muscular dystrophy
- haplotype analysis
- tandem DNA repeats
- subtelomeric regions
- clinical genetics
- molecular genetics
- neuromuscular disease
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Funding This research was supported in part by the National Institutes of Health (NS04885 to M.E). Some of the cultured cells from FSHD patients were provided by the Tissue and Cell Culture Repository at The University of Iowa, a component of the Iowa Wellstone Muscular Dystrophy Cooperative Research Center, (NIH NS053672).
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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