A novel ASCC1 splice-site variant broadens the phenotypic spectrum of spinal muscular atrophy with congenital bone fractures type 2.

Spinal muscular atrophy with congenital bone fractures type 2 (SMABF2) is an ultra-rare neuromuscular disorder caused by pathogenic variants affecting the ASC-1 complex, most commonly ASCC1. The disorder is typically characterized by severe congenital hypotonia, prenatal or congenital fractures, and early respiratory failure. We report a girl with a novel homozygous intronic donor-site variant, c.95+5G>C, in ASCC1. In contrast to the classic SMABF2 phenotype, she had no congenital fractures and survived until 7 years of age. Her clinical presentation included generalized hypotonia, areflexia, minimal spontaneous movements, dysmorphic features related to fetal hypomobility, progressive respiratory insufficiency requiring tracheostomy and gastrostomy, and cardiac involvement. This case expands both the genetic and phenotypic spectrum of ASCC1-associated disease. The comparatively prolonged survival and absence of congenital fractures suggest that not all ASCC1 variants result in a fully loss-of-function phenotype. However, this interpretation remains hypothetical because functional RNA studies were not performed.