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.

中文翻译：

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SMN1、SMN2和NAIP基因在SMA患者预后中的遗传模式

脊髓性肌萎缩症 (SMA) 是人类囊性纤维化后最常见的常染色体隐性遗传疾病。根据发病年龄和疾病严重程度将其分为五个临床等级。尽管 SMN1 被确定为 SMA 疾病决定基因，但映射到 5q13 的修饰基因被确认在确定疾病严重程度方面发挥关键作用，并用作 SMA 治疗的靶点。在这项研究中，我们确定了具有不同临床表型并具有 SMN1 纯合缺失的 SMA 埃及患者的 SMN2 拷贝数和 NAIP 缺失状态。我们旨在寻找包括 SMN1、SMN2 和 NAIP 基因型在内的预后遗传模式，以确定患者的临床 SMA 类型，以帮助进行遗传咨询和产前诊断。随着疾病严重程度的增加，SMN2基因外显子7的拷贝数变异（CNV）显着降低。在 60% (12/20) 的 I 型 SMA 和 73% (8/11) 的 III 型 SMA 病例中检测到 NAIP 外显子 5 的纯合缺失。结合 SMN2 和 NAIP 基因的数据显示了 8 种基因型。具有 D2 基因型（0 份 NAIP 和 2 份 SMN2）的患者可能患有 I 型 SMA。II 型 SMA 患者大多没有 NAIP 纯合缺失和 2 个 SMN2 拷贝。然而，具有 N3 基因型（> 1 个拷贝的 NAIP 和 3 个拷贝的 SMN2）和具有 D3 基因型（0 个拷贝的 NAIP 和 > 3 个 SMN2 拷贝）的患者具有 III 型 SMA。SMN2 和 NAIP 是最重要的修饰基因，其拷贝数可以影响 SMA 的严重程度。我们得出结论，为表型确定提供预后遗传模式的修饰基因组合比仅使用 SMN2 基因外显子 7 的 CNV 更可取。SMN2 外显子 7 的 CNV 对预测患者对基因治疗的反应非常重要。另一方面，仅 NAIP 基因外显子 5 的缺失不足以预测 SMA 的严重程度。