Vorster Elana, Essop Fahmida B, Rodda John L, Krause Amanda
National Health Laboratory Service and School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
Department of Paediatrics, University of the Witwatersrand, Johannesburg, South Africa.
Front Genet. 2020 Feb 13;11:54. doi: 10.3389/fgene.2020.00054. eCollection 2020.
Spinal muscular atrophy (SMA) is a neuromuscular disorder, characterized by muscle atrophy and impaired mobility. A homozygous deletion of survival motor neuron 1 (), exon 7 is the main cause of SMA in ~94% of patients worldwide, but only accounts for 51% of South African (SA) black patients. and its highly homologous centromeric copy, survival motor neuron 2 (, are located in a complex duplicated region. Unusual copy number variations (CNVs) have been reported in black patients, suggesting the presence of complex pathogenic rearrangements. The aim of this study was to further investigate the genetic cause of SMA in the black SA population. Multiplex ligation-dependent probe amplification (MLPA) testing was performed on 197 unrelated black patients referred for SMA testing (75 with a homozygous deletion of , exon 7; 50 with a homozygous deletion of , exon 7; and 72 clinically suggestive patients with no homozygous deletions). Furthermore, 122 black negative controls were tested. For comparison, 68 white individuals (30 with a homozygous deletion of , exon 7; 8 with a homozygous deletion of , exon 7 and 30 negative controls) were tested. Multiple copies (>2) of , exon 7 were observed in 50.8% (62/122) of black negative controls which could mask heterozygous deletions and potential pathogenic CNVs. MLPA is not a reliable technique for detecting carriers in the black SA population. Large deletions extending into the rest of and neighboring genes were more frequently observed in black patients with homozygous , exon 7 deletions when compared to white patients. Homozygous , exon 7 deletions were commonly observed in black individuals. No clear pathogenic CNVs were identified in black patients but discordant copy numbers of exons suggest complex rearrangements, which may potentially interrupt the gene. Only 8.3% (6/72) of clinically suggestive patients had heterozygous deletions of , exon 7 (1:0) which is lower than previous SA reports of 69.5%. This study emphasizes the lack of understanding of the architecture of the region as well as the cause of SMA in the black SA population. These factors need to be taken into account when counseling and performing diagnostic testing in black populations.
脊髓性肌萎缩症（SMA）是一种神经肌肉疾病，其特征为肌肉萎缩和运动功能受损。生存运动神经元1（SMN1）外显子7的纯合缺失是全球约94%患者SMA的主要病因，但仅占南非（SA）黑人患者的51%。SMN1及其高度同源的着丝粒拷贝生存运动神经元2（SMN2）位于一个复杂的重复区域。已有报道称黑人患者存在异常的拷贝数变异（CNV），提示存在复杂的致病重排。本研究的目的是进一步探究南非黑人人群中SMA的遗传病因。对197名因SMA检测前来就诊的无亲缘关系的黑人患者（75名SMN1外显子7纯合缺失；50名SMN2外显子7纯合缺失；72名临床疑似但无纯合缺失的患者）进行了多重连接依赖探针扩增（MLPA）检测。此外，还检测了122名黑人阴性对照。作为对照，检测了68名白人个体（30名SMN1外显子7纯合缺失；8名SMN2外显子7纯合缺失以及30名阴性对照）。在50.8%（62/122）的黑人阴性对照中观察到SMN1外显子7存在多个拷贝（>2），这可能会掩盖杂合缺失和潜在的致病CNV。MLPA并非检测南非黑人人群携带者的可靠技术。与白人患者相比，在SMN1外显子7纯合缺失的黑人患者中，更频繁地观察到延伸至SMN1其余部分和邻近基因的大片段缺失。在黑人个体中常见SMN1外显子7纯合缺失。在黑人患者中未发现明确的致病CNV，但外显子拷贝数不一致提示存在复杂重排，这可能会潜在地中断SMN1基因。临床疑似患者中仅有8.3%（6/72）存在SMN1外显子7杂合缺失（1:0），低于南非此前69.5%的报道。本研究强调了对SMN1区域结构以及南非黑人人群中SMA病因缺乏了解。在为黑人人群提供咨询和进行诊断检测时，需要考虑这些因素。
