A homozygous missense variant in the YG box domain in an individual with severe spinal muscular atrophy: a case report and variant characterization

The vast majority of severe (Type 0) spinal muscular atrophy (SMA) cases are caused by homozygous deletions survival motor neuron 1 ( SMN1 ). We report a case in which the patient has two copies but clinically presents as Type 0 SMA. is an African American male carrying maternally inherited missense variant (c.796T>C) cis -oriented duplication on one chromosome and deletion other (genotype: 2*+0). Initial extensive genetic workups including exome sequencing were negative. Deletion analysis used initial testing for SMA also failed to detect . Because high clinical suspicion, diagnosis was finally confirmed based full-length sequencing. initially treated with risdiplam later gene therapy onasemnogene abeparvovec at 5 months without complications. patient’s weakness stabilized mild improvement. now 28 old remains stable diffusely weak, respiratory ventilatory support. This highlights challenges non-deletion genotype provides example demonstrating that disruption functional SMN protein polymerization through amino acid change YG-box domain represents little known important pathogenic mechanism Clinicians need be mindful about limitations current diagnostic approach detecting genotypes.