The phenotypic spectrum and genetic determinants of severe spinal muscular atrophy in individuals with a single SMN2 copy: an international retrospective observational study.

内容摘要

Spinal Muscular Atrophy (SMA) is a phenotypically heterogenous disease. The Survival Motor Neuron 2 (SMN2) gene copy number can partially predict the clinical severity of SMA, with a single SMN2 copy generally associated with the most severe phenotypes. The aim of this retrospective observational study was to explore the spectrum of phenotypes associated with one SMN2 copy and the possible association with genotype and outcome. We conducted a retrospective observational study of individuals with genetically confirmed SMA (biallelic Survival Motor Neuron 1 [SMN1] variants) and one SMN2 copy, recruited from 36 Italian neuromuscular centres and additional 28 centres from nine other countries (Austria, Belgium, Brazil, Chile, Germany, Netherlands, Spain, United Kingdom and United States) between January 2015 and November 2025.Individuals were included irrespective of age or phenotype; those with incomplete genetic data or confounding diagnoses were excluded. The primary outcome was the phenotypic spectrum associated with a single SMN2 copy, including clinical severity, genotype, treatment exposure, and survival at last follow-up. Sixty-five individuals with one SMN2 copy were included. Neonatal onset was observed in 50/65 (77%). The predominant phenotype was type 0 (39/50, 78%), followed by type 1.1 (6/50, 12%). Five individuals with neonatal onset had prenatal signs (reduced foetal movements and cardiac malformation), but no contractures reported. All individuals with neonatal onset had homozygous deletions of SMN1. The remaining 15/65 (23%) had later onset, with milder phenotypes and all but two presented either with an heterozygous SMN1 deletion associated with a point mutation, or with c.859G>C(p.Gly287Arg) variant in SMN2. Our findings confirm that type 0 is the most frequent phenotype associated with one SMN2 copy, but the boundaries between neonatal-onset phenotypes appear to be fluid. The individuals with one SMN2 copy with milder phenotypes carried variants known to mitigate disease severity. Further prospective studies are needed to better define genotype-phenotype correlations and inform treatment decisions in this population. Some of the data in this study originate from disease registries at least partially funded by Biogen, Novartis and Roche.