FSHD is a prevalent progressive myopathy caused by misexpression of a double homeodomain transcription factor, DUX4, in skeletal muscle.19,20 DUX4 is normally expressed during embryonic development, where it activates the first wave of zygotic gene expression.21–23 In individuals with FSHD, DUX4 is reactivated in muscle and induces apoptotic death leading to atrophy.24–27 We have shown that DUX4 misexpression in muscle cells causes rapid and acute NMD inhibition followed by proteotoxic stress and, eventually, translation inhibition.18,28. Here, DUX4 is linked to facioscapulohumeral muscular dystrophy.