À l’heure actuelle, le diagnostic de DMFSH2 reste complexe car nécessitant un génotypage complet du locus D4Z4 et un test de méthylation spécifique. En effet, à la différence des patients DMFSH1 qui présentent une contraction pathogène des unités répétées D4Z4 portées par l’extrémité du chromosome 4 permissif (4QA), les patients DMFSH2 exprimant le phénotype clinique présentent : (1) un nombre normal d’unités répétées sur les chromosomes 4 (>11), (2) au moins un allèle du chromosome 4 de type 4QA et (3) une hypométhylation significative des loci D4Z4 sur les chromosomes 4 et 10.

L’étude du mode de transmission de la DMFSH2 suggère une hérédité digénique, l’hypométhylation seule n’étant pas suffisante à l’expression du phénotype clinique. L’identification des gènes et des mécanismes épigénétiques à la base de cette maladie facilitera le diagnostic de ces patients et confirmera les hypothèses sur le mécanisme physiopathologique commun à ces deux maladies.

In recent years, the advances of knowledge in clinical, genetic and epigenetic features of facioscapulohumeral muscular dystrophy (FSHD) allowed the identification of two forms of FSHD, the classical autosomal dominant FSHD type 1, and FSHD type 2 characterized by an identical clinical phenotype but associated with a different (epi)genetic defect.

In the large majority of FSHD1 patients, the identification of D4Z4 pathogenic contraction on a permissive chromosome 4 is sufficient for diagnosis, while FSHD2 diagnosis is complicated by the fact that the genetic defect associated with this disease is not known yet and a complete D4Z4 genotype and a D4Z4 specific methylation test are required. Indeed, FSHD2 patients display a non-contracted D4Z4 allele on chromosomes 4, at least one permissive chromosome 4QA and a profound hypomethylation of both chromosomes 4 and 10. A common pathophysiological pathway has been hypothesized for FSHD1 and FSHD2 in order to explain the identical clinical phenotype and the highly similar epigenetic changes found in patients affected by these diseases. According to this hypothesis, chromatin relaxation – due to pathogenic D4Z4 contraction in FSHD1 patients, and to important hypomethylation of this locus in FSHD2 patients – would allow the last D4Z4 unit to encode for a toxic DUX4 transcript. This transcript would be stable only when encoded from a permissive chromosome 4 carrying a polyadenylation signal immediately distal to the last D4Z4 unit on chromosome 4.

Since, to express clinical phenotype, FSHD2 patients have to carry both 4QA chromosome and hypomethylated D4Z4 on chromosomes 4 and 10, digenic transmission has been hypothesized for this disease. The identification of the gene(s) and the exact epigenetic pathway underlining this disease will be mandatory to increase the rate of diagnosis for FSHD2 patients and to confirm the hypothesis of a common FSHD1 and FSHD2 pathophysiological pathway involving DUX4 gene.

The identification, among patients carrying a FSHD phenotype, of FSHD2, a new disease with distinct (epi)genetic features but having a common pathophysiological pathway with FSHD1, suggests the possibility of developping new therapeutic strategies suitable for both diseases.