The aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number.

Four hundred fifty Brazilian patients with SMA were included in a retrospective study, and clinical data were analyzed compared with genetic data; the SMN2 copy number was obtained by multiplex ligation-dependent probe amplification and pathogenic variants in SMN1 by next-generation sequencing.

Four hundred two patients (89.3%) presented homozygous exon 7-SMN1 deletion, and 48 (10.7%) were compound heterozygous for the common deletion in one allele and a point mutation in the other allele. Recurrent variants in exons 3 and 6 (c.460C>T, c.770_780dup and c.734_735insC) accounted for almost 80% of compound heterozygous patients. Another recurrent pathogenic variant was c.5C>G at exon 1. Patients with c.770_780dup and c.734_735insC had a clinical phenotype correlated with SMN2 copy number, whereas the variants c.460C>T and c.5C>G determined a milder phenotype independently of the SMN2 copies.

Patients with specific pathogenic variants (c.460C>T and c.5C>G) presented a milder phenotype, and the SMN2 copy number did not correlate with disease severity in this group.

该研究的目的是报告大量脊髓性肌萎缩症 (SMA) 患者中生存运动神经元 1 ( SMN1 ) 基因中纯合和复合杂合变异的比例，并将疾病的严重程度与存在SMN1和SMN2拷贝数的特定基因内变异。

一项回顾性研究纳入了 450 名巴西 SMA 患者，将临床数据与遗传数据进行比较分析；SMN2拷贝数是通过二代测序在SMN1中通过多重连接依赖性探针扩增和致病变异获得的。

402 名患者 (89.3%) 出现纯合子外显子 7 - SMN1缺失，48 名 (10.7%) 是一个等位基因的共同缺失和另一个等位基因的点突变的复合杂合子。外显子 3 和 6（c.460C>T、c.770_780dup 和 c.734_735insC）中的复发性变异占复合杂合子患者的近 80%。另一种复发性致病变异是外显子 1 的 c.5C>G。c.770_780dup 和 c.734_735insC 的患者具有与SMN2拷贝数相关的临床表型，而变异 c.460C>T 和 c.5C>G 确定较温和表型独立于SMN2拷贝。

具有特定致病变异（c.460C>T 和 c.5C>G）的患者表现出较温和的表型，并且该组中SMN2拷贝数与疾病严重程度无关。