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Spinal muscular atrophy (SMA) is the most common autosomal recessive disorder in humans after cystic fibrosis. It is classified into five clinical grades based on age of onset and severity of the disease. Although SMN1 was identified as the SMA disease-determining gene, modifier genes mapped to 5q13 were affirmed to play a crucial role in determination of disease severity and used as a target for SMA therapy. In this study, we determined SMN2 copy number and NAIP deletion status in SMA Egyptian patients with different clinical phenotypes and had homozygous deletion of SMN1. We aimed at finding a prognostic genetic pattern including SMN1, SMN2, and NAIP gene genotypes to determine the clinical SMA type of the patient to help in genetic counseling and prenatal diagnosis. Copy number variations (CNVs) of exon 7 of SMN2 gene were significantly decreased with the increase in disease severity. Homozygous deletion of exon 5 of NAIP was detected in 60% (12/20) of type I SMA and in 73% (8/11) of type III SMA cases. Combining the data of the SMN2 and NAIP genes showed 8 genotypes. Patients with D2 genotype (0 copies of NAIP and 2 copies of SMN2) were likely to have type I SMA. Type II SMA patients mostly had no homozygous deletion of NAIP and 2 copies of SMN2. However, patients with N3 genotype (> 1 copy of NAIP and 3 copies of SMN2) and patients with D3 genotype (0 copies of NAIP and > 3 copies of SMN2) had type III SMA. SMN2 and NAIP are the most important modifier genes whose copy numbers can affect the severity of SMA. We concluded that the combination of modifier genes to provide prognostic genetic pattern for phenotype determination is preferable than using CNVs of exon 7 of SMN2 gene only. CNVs of exon 7 of SMN2 are of high importance to predict patients’ response to genetic therapy. On the other hand, deletion of exon5 of NAIP gene alone is not a sufficient predictor of SMA severity.

Genetic pattern of SMN1, SMN2, and NAIP genes in prognosis of SMA patients