Genomic Vision’s Technology offers a powerful diagnostic solution for

Facio-scapulo-humeral muscular dystrophy (FSHD)

A usually autosomal dominant, inherited form of muscular dystrophy

Facio-scapulo-humeral muscular dystrophy (FSHD) is the third most prevalent muscular hereditary myopathy. FSHD manifests as atrophy and weakness in the face, shoulders, and ambulatory muscles. There is great variability in clinical severity, from a severe infantile form to individuals who remain asymptomatic throughout their lives.

This autosomal dominant disease is thought to affect 1 out of 10,000 to 1 out of 20,000 people. The actual number of individuals with FSHD worldwide is 870,000, which could be significantly higher due to undiagnosed cases. About 70% of FSHD patients inherit the disease from a parent, while 30% of the cases are sporadic and associated to de novo mutations. Approximately 95% of FSHD cases are known as Type 1, the remaining 5% of FSHD cases called Type 2.

FSHD1 is associated with the contraction of a repeat array (D4Z4) at the sub-telomeric end of the chromosome 4

The repeated sequence, 3.3 kb-D4Z4, is present on 4q as well as 10q chromosomes and the repeat arrays usually comprise from one to hundreds of copies of tandem repeated D4Z4.

Two haplotypes of 4q chromosomes exist, qA and qB, diverging in their telomeric extremities, with a roughly 50% ratio for both 4qA and 4qB. The disease segregates with short (less than ten copies) 4qA alleles.

All individuals with FSHD1 have a D4Z4 allele of between one and ten repeat units associated to FSHD1. 4qB and 10q alleles of any size are not pathogenic.

Complex diagnosis due to the presence of a virtually identical repeat array on chromosome 10 and the high frequency of mosaicism 

The diagnosis of FSHD1 is technically challenging due to the repetitive nature of the D4Z4 sequence. The detection is further complicated by the presence of a homologous repeat array on chromosome 10. There is also a high frequency of somatic mosaicism that occurs for the FSHD1 contraction probably through a mitotic event during early embryonic development. The frequency of the mosaic allele and the affected cell types are possibly related to the phenotypic outcome of the disease and require an accurate recognition.

Current genetic tests are based on Southern blotting, which uses pulse field gel electrophoresis or, less accurately, linear gel, which is laborious and can render data that is difficult to interpret as it yields uncertain results when D4Z4 repeats on chromosomes 4 and 10 cannot be distinguished. The successive failures in the detection of complex rearrangements, mosaicisms and variants can be responsible for ambiguous diagnostic results.

An assay based on Genomic Vision’s Technology

Clear and precise identification of FSHD1-specific repeats within their specific genomic environment

Following the successful clinical trials in partnership with Prof Nicolas Lévy at La Timone Hospital, Marseille (reference laboratory for genetic testing) and with the University of the Mediterranean, Marseille, Genomic Vision launched the commercialization of the test in 2013. Our FHSD diagnostic assay is already used at La Timone Hospital in France and by Quest Diagnostics in the United States.