Genetic Diagnosis of Facioscapulohumeral Muscular Dystrophy Type 1 Using Rare Variant Linkage Analysis and Long Read Genome Sequencing

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.