Optical Genome Mapping – FSHD1

Clinical Information

Facioscapulohumeral muscular dystrophy (FSHD) is a highly variable disorder characterized by progressive and often asymmetric muscle weakness in the face, scapular stabilizers, shoulders, arms, lower legs, and hip girdle. Two types of FSHD have been described: FSHD1 and FSHD2.

FSHD1 is the most common form and is observed in >95% of individuals diagnosed with FSHD, whereas FSHD2 is observed in the remaining <5% of cases. Both FSHD1 and FSHD2 are caused by abnormal epigenetic activation of the DUX4 gene, a transcription factor that is normally silenced. DUX4 is either encoded with a polyadenylation sequence (termed the 4qA permissive haplotype) or without a polyadenylation sequence (4qB non-permissive haplotype). Contraction of the D4Z4 repeat array on the permissive 4qA haplotype is consistent with a diagnosis of, or a predisposition to develop FSHD1. In FSHD2, hypomethylation of the D4Z4 repeat array can be the result of a heterozygous pathogenic variant in SMCHD1 or DNMT3B, or biallelic pathogenic variants in LRIF1, in the presence of a 4qA permissive allele.

Technical Information

Optical Genome Mapping analysis of the D4Z4 repeat region of chromosome 4q35 is performed to assess for the pathogenic contraction of the repeat array on the 4qA permissive haplotype. Characterization of the D4Z4 repeat region is assisted by the concurrent analysis of the benign 10q subtelomeric region. Normal alleles (≥11 repeat units); contracted, reduced-penetrance alleles (8-10 repeat units); and contracted, full-penetrance alleles (≤7 repeat units) will be reported.

The most common cause of FSHD1 is a pathogenic contraction of the D4Z4 repeat array on a permissive 4qA haplotype. If a contraction is not identified, then the test will automatically reflex to evaluate structural variants in genes associated with FSHD2, including SMCHD1, DNMT3B, and LRIF1, if at least one 4qA permissive haplotype is detected. Please note that this test does not include sequencing of the SMCHD1, DNMT3B, and LRIF1 genes. Additionally, this test does not include methylation analysis of the D4Z4 array. OGM FSHD1 only includes evaluation of the D4Z4 repeat region and structural variants within the SMCHD1, DNMT3B, and LRIF1 genes in the presence of a permissive haplotype. The remainder of the genome will not be assessed for structural variants.

OGM Complete can be ordered for a genome-wide structural variant analysis at an additional charge. A focused NGS can be added using the existing sample to detect sequence variants in the SMCHD1, DNMT3B, and LRIF1 genes, also at an additional charge.

Specimen Requirements

The accepted sample type is 3-4 ml of fresh or frozen blood collected in an EDTA (purple top) tube. Ultra-high molecular weight DNA is required for OGM analysis and can only be extracted if specimen and transport requirements are met. Blood kits are available by request.

Transport Instructions

Ship the blood sample overnight in an insulated container with cold packs no colder than 4°C (refrigerated temperature). Incidental freezing and thawing due to cold packs cooler than 4°C may diminish DNA quality. Frozen blood should be shipped on dry ice.