Single Nucleotide Variants in a Cohort of Individuals With Spinal Muscular Atrophy.

Background And Objectives: Spinal muscular atrophy 5q (SMA) is a motor neuron disorder caused by recessive pathogenic variants in the gene, which encodes the survival motor neuron (SMN) protein. While the majority of patients with SMA exhibit homozygous deletions in , a minority (2%-5%) of patients with SMA harbor an deletion plus a single nucleotide variant on the second allele, which can be identified through direct gene sequencing. The comprehensive characterization of patients with SMA is increasingly crucial considering emerging therapies and newborn screening initiatives.

Methods: Over the past 20 years, we confirmed a molecular diagnosis of SMA in 149 patients consisting of 138 postnatal and 11 prenatal cases, through a quantitative molecular approach (real-time PCR and/or multiplex ligation-dependent probe amplification) associated with direct sequencing.

Results: We identified homozygous deletions in 142 probands (95%). The remaining 7 patients (5%) displayed heterozygous deletion in compound with a different molecular defect. Notably, 1 patient presented with an intronic variant necessitating mRNA transcript analysis, a process that extended the time to diagnosis.

Discussion: The identification of small pathogenic variants in patients with SMA is of paramount importance for enhancing diagnosis and prognosis, deciphering response variations to existing treatments, and designing novel therapies tailored to address these genetic variants. We propose a paradigm shift from current guidelines, particularly for patients with a heterozygous deletion and a clinically compatible SMA phenotype, especially when reduced SMN transcript levels are evident. In such cases, expedited therapy initiation, including reversible treatments like nusinersen or risdiplam, is recommended without waiting for the completion of the molecular testing, thus minimizing delays in crucial therapeutic interventions.