Abstract
BackgroundSpinal 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.ResultsCopy 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.ConclusionSMN2 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.
Highlights
Spinal muscular atrophy (SMA) is the most common autosomal recessive disorder in humans after cystic fibrosis
Our results showed that neuronal apoptosis inhibitory protein (NAIP) deletion alone was not a good predictor of SMA severity as homozygous deletion was detected in 60% (12/20) of type I SMA and in 73% (8/11) of type III SMA, which was much lower than the published ratios in other populations
We implemented PCR-RFLP, multiplex PCR, and realtime PCR to analyze the correlation between Copy number variation (CNV) of survival motor neuron 1 (SMN1), NAIP, and Survival motor neuron 2 gene (SMN2) genes and the SMA phenotype in Egyptian patients
Summary
Spinal muscular atrophy (SMA) is the most common autosomal recessive disorder in humans after cystic fibrosis. Type I SMA patients (Werdnig-Hoffmann disease) have an age of onset before 6 months at which hypotonia can be observed followed by progressive weakness which is worse proximally than distally and is initially more obvious in the legs making it difficult for them to sit up. They do not have the ability to sit without support and their life expectancy is less than 2 years; because muscle weakness affects the chest wall and diaphragm causing breathing difficulty and Hassan et al Egyptian Journal of Medical Human Genetics (2020) 21:4 respiratory failure. They exhibit slowly progressive limb weakness and associated with a normal life expectancy
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