Variant Update on ASCC1: Characterization of the First Homozygous Missense Variant Involved in Prenatal-Onset Spinal Muscular Atrophy With Congenital Bone Fractures 2

Spinal muscular atrophy with congenital bone fractures 2 is a rare and severe autosomal recessive neuromuscular disorder caused by pathogenic variants in ASCC1. This condition characterized by prenatal onset of severe hypotonia with fetal hypokinesia and congenital contractures results in arthrogryposis multiplex congenita, and increased incidence of prenatal fractures. To date, only truncating variants, loss of function and splicing variants have been described. Here, we report the first homozygous missense variant in ASCC1 identified prenatally in two full siblings with fetal akinesia deformation sequence. This variant affects a highly conserved residue within the RNA-ligase-like domain and leads to a nearly total absence of ASCC1 protein in muscle. This report broadens the knowledge on the pathogenesis of this disorder showing that missense variants should also be considered. It also highlights the importance of precise ultrasound examination combined with molecular genetic testing in the prenatal diagnosis of this severe neuromuscular disorder.