The difficulty of interpreting SMCHD1 gene variants in FSHD

Clinicians and geneticists from the French network dedicated to facioscapulohumeral muscular dystrophy (FSHD), which includes clinicians from the Institut de Myologie, have provided an update on a rarer form of FSHD type 2 linked to the SMCHD1 gene:

• the sequencing data and methylation studies of 54 FSHD1-negative patients were collected and analysed,
• all patients had a number of residual D4Z4 fragments greater than 10,
• 48 were carriers of a pathological variant of SMCHD1 and 6 were haemizigotes for the 18p32 region containing the SMCHD1 gene,
• correlation studies showed that SMCHD1 variants could only really be considered as pathological if methylation was reduced by at least 40%.
• a diagnostic algorithm allows all these factors to be taken into account in order to confirm the diagnosis of FSHD2 with certainty.

Despite real progress, the authors stress the difficulty of these molecular data in FSHD in general and in FSHD2 in particular.

 

Gérard L, Delourme M, Tardy C, Ganne B, Perrin P, Chaix C, Trani JP, Eudes N, Laberthonnière C, Bertaux K, Missirian C, Bassez G, Behin A, Cintas P, Cluse F, De La Cruz E, Delmont E, Evangelista T, Fradin M, Hadouiri N, Kouton L, Laforêt P, Lefeuvre C, Magot A, Manel V, Nectoux J, Pegat A, Sole G, Spinazzi M, Stojkovic T, Svahn J, Tard C, Thauvin C, Verebi C, Salort Campana E, Attarian S, Nguyen K, Badache A, Bernard R, Magdinier F. SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance. Eur J Hum Genet. 2024 Dec 26. doi: 10.1038/s41431-024-01781-x. Epub ahead of print. PMID: 39725690.