The analysis of the association between the copy numbers of survival motor neuron gene 2 and neuronal apoptosis inhibitory protein genes and the clinical phenotypes in 40 patients with spinal muscular atrophy

Abstract

In this article, the correlation between the copy number of survival motor neuron 2 (SMN2) gene, neuronal apoptosis inhibitory protein (NAIP), and the phenotype of spinal muscular atrophy patients were analyzed.Forty patients with spinal muscular atrophy (SMA) were included in the study at the Department of Medical Genetics of the First People's Hospital and the Department of Neurology of the Second People's Hospital in Yunnan Province from January 2012 to September 2018. Multiplex ligation-dependent probe amplification assay was performed to determine the copy numbers of SMN2 and NAIP genes. Statistical analysis was performed to determine the correlation between copy numbers of the SMN2 and NAIP genes and the clinical phenotypes of SMA.Our results show that among the 40 SMA patients, there were 13 type I cases, 16 type II cases and 11 type III cases. A total of 37 patients possessed a homozygous deletion of SMN1 exons 7 and 8, while the other 3 SMA patients possessed a single copy of SMN1 exon 8. There was no correlation between SMA subtypes and the deletion types of SMN1 exon 7 and 8 (P = .611). The percentage of 2, 3, and 4 copies of SMN2 exon 7 was 25.0%, 62.5%, and 12.5%, respectively. The percentage of 0, 1, and 2 copies of NAIP exon 5 was 10%, 57.5%, and 32.5%, respectively. The distributions of SMN2 and NAIP copy numbers among various SMA types were significantly different (all P < .05). Five combined SMN1-SMN2-NAIP genotypes were detected, of which 0-3-1 genotype had the highest proportion than the others, accounting for 42.5%. The copy number of SMN2 and NAIP gene had synergistic effect on SMA phenotype. The combined SMN1-SMN2-NAIP genotypes with fewer copies were associated with earlier onset age, higher mortality, and smaller average age at death in SMA patients. Therefore, we conclude that the copy number variance of SMN2 and NAIP is correlated with the SMA phenotype. Analysis of the copy number structure of the SMN1-SMN2-NAIP gene is helpful for SMA typing, disease prognosis prediction, and genetic counseling.

The Importance of Digging into the Genetics of SMN Genes in the Therapeutic Scenario of Spinal Muscular Atrophy

“…This model only differs from Calucho's correlations in type III patients, since it establishes the expected SMN2_CN to be 4 instead of 3 and 4 indistinctly [9]. In the recent literature, the correlation described by Calucho et al (2018) is mainly maintained [28][29][30][31][32], although some exceptions can be found. Interestingly, the proportion of type I patients with 3 SMN2 genes was increased in some cohorts, reaching 57% among SMA I patients, while Calucho's compilation reported only 23% [33,34].…”

Molecular Analysis of SMN2, NAIP and GTF2H2 Gene Deletions and Relation with Clinical Subtypes of Spinal Muscular Atrophy

“…But its role in pathogenesis has not been fully clear up yet (Ahn, Eun-ji, Yum, Mi-Sun 2016). In 2020, it was studied in 40 SMA patients in Yunnan Province, China, and it was demonstrated synergistic modi cation effects of the SMN2 and NAIP genes on the SMA phenotype (Zhang et al 2020).…”

“…SMA Type 4 occurs in the 20s or 30s and is the adult form of SMA. Compared to other types, the symptoms are milder, and SMA type 4 form is rarely seen (Zhang et al 2020).…”

Evaluation of Genotypes and Epidemiology of Spinal Muscular Atrophy in Greece: A Nationwide Study Spanning 24 Years

“…Consistent to previous studies, low SMN2 copies were strongly correlated with higher severity in patients with homozygous SMN1 deletions ( r = 0.78) [ 7, 12, 14, 19 ]. The secondary influence of low NAIP copies on the severity is also discussed in several studies; however data on the relative impact on the age of onset is not so well established) [ 20, 21 ]. With our study a statistically significant effect of NAIP gene copies was demonstrated when 0–1 copies were considered low, adjusted for SMN2 copies and gender.…”