Key result
Rare variant linkage analysis and ultra-long read sequencing map the locus and genotype the FSHD1 allele.
Why the study?
Facioscapulohumeral dystrophy type 1 requires a multimodal approach for complete molecular characterization of pathogenic genotypes.
Can ultra-long read genome sequencing and rare variant linkage analysis accurately map and genotype pathogenic alleles in a family with suspected FSHD1?
Observational (n=10)
No
Can ultra-long read genome sequencing and rare variant linkage analysis accurately map and genotype pathogenic alleles in a family with suspected FSHD1?
Ultra-long read genome sequencing combined with rare variant-based linkage analysis is an effective tool for mapping and genotyping pathogenic FSHD1 alleles.
Answers are grounded in this paper and cite their sources.
Demonstrates feasibility of long-read sequencing for FSHD1 in one family; leaves open validation before clinical adoption.
Facioscapulohumeral dystrophy type 1 (FSHD1) is a progressive, debilitating skeletal myopathy that requires a multimodal approach for complete molecular characterization of pathogenic genotypes. Here, we report genomic analyses of a family with suspected facioscapulohumeral dystrophy type 1 (FSHD1). We first performed short read genome sequencing, followed by parametric linkage analysis using rare variants to map the disease locus to a single 1.7 MB interval on chromosome 4q35.2 with a LOD score of 3.2. We then used ultra-long read genome sequencing as a single molecular test to genotype a pathogenic FSHD allele containing a 4qA permissive haplotype and 5 KpnI repeat units at the D4Z4 locus. These results demonstrate that genome-wide rare variant-based linkage analysis is a powerful tool for mapping disease loci in families and ultra-long read genome sequencing is capable of genotyping pathogenic FSHD1 alleles.
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Li et al. (2023) conducted an observational in Facioscapulohumeral Muscular Dystrophy Type 1 (FSHD1) (n=10). Ultra-long read genome sequencing and rare variant linkage analysis was evaluated on Mapping of the disease locus and genotyping of the pathogenic FSHD1 allele (LOD score 3.2). Rare variant-based linkage analysis mapped the disease locus to chromosome 4q35.2 with a LOD score of 3.2, and ultra-long read genome sequencing successfully genotyped the pathogenic FSHD1 allele.
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