Quantitative and structural features of the SMN1 and SMN2 genes in patients with spinal muscular atrophy 5q

Background. Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by loss of motor neurons. The cause of neurodegeneration is predominantly a homozygous deletion of the SMN1 gene, leading to a decrease in the synthesis of the SMN protein. The clinical picture of the disease is heterogeneous and varies depending on the age of onset and the ability to perform motor functions. Several genetic and molecular modifiers have been identified that are thought to influence the severity of SMA. One of the most proven factors is the number of copies of the SMN2 gene.

Aim. Description of quantitative and structural features of the SMN1 and SMN2 genes in patients with SMA 5q.

Materials and methods. The study included DNA samples from patients examined for the number of copies of the SMN1 and SMN2 genes at the Scientific and Methodological Center for Molecular Medicine, I.P. Pavlov First Saint Petersburg State Medical University, for the period from 2021 to 2022. Gene copy numbers were determined by multiplex ligation-dependent probe amplification using the SALSA MLPA P021 SMA kit (MRC Holland). We assessed an indirect parameter of aggressiveness (the age of the patient’s visit to the laboratory) to assess the severity of clinical manifestations of SMA. Statistical analysis was carried out using the statistical data processing program GraphPad Prism9.

Results. A statistically significant direct correlation was found when studying the relationship between the number of copies of the SMN2 gene and the age of molecular diagnosis (r = 0.3960, p <0.0001). An assessment of the significance of differences between individual groups of patients gave a statistically significant result: <0.0001 when comparing groups of patients with 2 and 3 copies; <0.0001 – with 2 and 4 copies; 0.0370 – with 3 and 4 copies. 9 % of patients had a hybrid SMN1/SMN2 structure. Therefore, the significance of differences between the age of molecular diagnosis of patients with homozygous deletion of SMN1 and the age of molecular diagnosis of patients with the hybrid SMN1/SMN2 gene between groups with the same number of copies of the SMN2 gene was assessed. A statistically significant result (p = 0.0070) was found between patients with SMN1 deletion + 2 copies of SMN2 and patients with the hybrid gene SMN1/SMN2 + 2 copies of SMN2.

Conclusion. The number of SMN2 gene copies correlates with the age of molecular diagnosis and indirectly predicts the age of SMA onset. The effect of the SMN1/SMN2 hybrid gene on the age of molecular diagnosis of SMA was comparable to the effect of the regular SMN2 gene.

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