MLPA analysis for molecular diagnosis of spinal muscular atrophy and correlation of 5q13.2 genes with disease phenotype in Egyptian patients

Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease representing the most prevalent monogenic cause of infant mortality. It results from the loss of SMN1 gene, but retention of its paralog SMN2 whose copy number can modulate the disease severity and guide the therapeutic regimen. Methods For SMA molecular analysis, 236 unrelated Egyptian patients were enrolled at our institution. The Multiplex ligation-dependent probe amplification analysis (MLPA) was applied to investigate the main genetic defect in the enrolled patients ( SMN1 loss) and to determine a possible genotype–phenotype correlation between the copy number of other genes in the SMN locus (5q13.2) and disease severity in Egyptian patients with SMA. A small cohort of healthy subjects ( n = 57) was also included to investigate the possible differences in the distributions of SMN2 and NAIP genes between patients and healthy individuals. Results Disease diagnosis was confirmed in only 148 patients (62.7%) highlighting the clinical overlapping of the disease and emphasizing the importance of molecular diagnosis. In patients with homozygous SMN1 loss, the disease was mediated by gene deletion and conversion in 135 (91.2%) and 13 (8.8%) patients, respectively. In the study cohort, SMN2 and NAIP copy numbers were inversely correlated with disease severity. However, no significant association was detected between GTF2H2A and SERF1B copy numbers and patient phenotype. Significant differences were demonstrated in the copy numbers of SMN2 and NAIP between SMA patients and healthy subjects. Conclusion Molecular analysis of SMA is essential for disease diagnosis. Consistent with previous studies on other populations, there is a close relationship between SMN2 and NAIP copy numbers and clinical phenotype. Additionally, potential differences in these two genes distributions are existing between patients and healthy subjects. National program for carrier screening should be established as a preventive disease strategy. On the other hand, neonatal testing would provide accurate estimation for disease incidence.