Objective Recently, the ASC-1 complex has been identified as a mechanistic link between ALS and spinal muscular atrophy (SMA), and three mutations of the ASC-1 gene TRIP4 have been associated with SMA or congenital myopathy. Our goal was to define ASC-1 neuromuscular function and the phenotypical spectrum associated with TRIP4 mutations. Methods Clinical, molecular, histological and MRI studies in 5 families with 7 novel TRIP4 mutations. FACS and Western blot in patient-derived fibroblasts and muscles and in Trip4 knocked-down C2C12 cells. Results All mutations caused ASC-1 protein depletion. The clinical phenotype was purely myopathic, ranging from lethal neonatal to mild ambulatory adult patients. It included early-onset axial and proximal weakness, scoliosis, rigid spine, dysmorphic facies, cutaneous involvement, respiratory failure and, in the older cases, dilated cardiomyopathy. Muscle biopsies showed multiminicores, nemaline rods, cytoplasmic bodies, caps, central nuclei, rimmed fibers and/or mild endomysial fibrosis. ASC-1 depletion in C2C12 and in patient-derived fibroblasts and muscles caused accelerated proliferation, altered expression of cell cycle proteins and/or shortening of the G0/G1 cell cycle phase leading to cell size reduction. Interpretation Our results expand the phenotypical and molecular spectrum of TRIP4-associated disease to include mild adult forms with or without cardiomyopathy, associate ASC-1 depletion with primary pure muscle involvement and establish TRIP4 as a causative gene for several congenital muscle diseases including nemaline, core, centronuclear or cytoplasmic-body myopathies. They also identify ASC-1 as

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