The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease
The Latin American experience with a next generation sequencing genetic panel for recessive limb-girdle muscular weakness and Pompe disease
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DOI：
10.1186/s13023-019-1291-2
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发表时间：
2020-01-13
影响因子：
3.7
通讯作者：
Araujo, Roberto
中科院分区：
文献类型：
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作者：
Bevilacqua, Jorge A.;Guecaimburu Ehuletche, Maria del Rosario;Araujo, Roberto
肢带型肌营养不良症（Limb-girdle muscular dystrophy，LGMD）是一组具有异质性遗传病因的神经肌肉疾病，有30多个直接相关基因。LGMD的特征在于涉及肩部和骨盆带的进行性肌肉无力。近端肌无力（PMW）患者的一个重要鉴别诊断是迟发性庞贝氏症（LOPD），这是一种罕见的神经肌肉糖原累积障碍，除了PMW外，还经常出现早期呼吸功能不全。本拉丁美洲患者研究纳入了有或无呼吸道症状的PMW患者，以评价纳入的LGMD隐性（R）和LOPD相关基因的变异特征以及该患者人群中每种基因的变异频率。结果2016年和2017年期间，拉丁美洲（巴西、阿根廷、秘鲁、厄瓜多尔、墨西哥和智利）的20多家机构招募了2103名个人。根据拉丁美洲报告的疾病频率，在10个基因组（ANO 5、CAPN 3、DYSF、FKRP、GAA、SGCA、SGCB、SGCD、SGCG、TCAP）中研究了9种常染色体隐性LGMD和庞贝氏病。用Illumina的NextSeq 500进行测序，并根据ACMG指南对变体进行分类;致病性和可能致病性被视为一类（P），并描述了未知意义的变体（VUS）。在55.8%的患者中发现了遗传变异，其中16%接受了明确的分子诊断; 39.8%患有VUS。9例患者被确定为庞贝氏症。结论该结果证实了该靶向基因组的有效性，以及将庞贝氏症纳入PMW患者鉴别诊断的重要性。
Background Limb-girdle muscular dystrophy (LGMD) is a group of neuromuscular disorders of heterogeneous genetic etiology with more than 30 directly related genes. LGMD is characterized by progressive muscle weakness involving the shoulder and pelvic girdles. An important differential diagnosis among patients presenting with proximal muscle weakness (PMW) is late-onset Pompe disease (LOPD), a rare neuromuscular glycogen storage disorder, which often presents with early respiratory insufficiency in addition to PMW. Patients with PMW, with or without respiratory symptoms, were included in this study of Latin American patients to evaluate the profile of variants for the included genes related to LGMD recessive (R) and LOPD and the frequency of variants in each gene among this patient population. Results Over 20 institutions across Latin America (Brazil, Argentina, Peru, Ecuador, Mexico, and Chile) enrolled 2103 individuals during 2016 and 2017. Nine autosomal recessive LGMDs and Pompe disease were investigated in a 10-gene panel (ANO5, CAPN3, DYSF, FKRP, GAA, SGCA, SGCB, SGCD, SGCG, TCAP) based on reported disease frequency in Latin America. Sequencing was performed with Illumina's NextSeq500 and variants were classified according to ACMG guidelines; pathogenic and likely pathogenic were treated as one category (P) and variants of unknown significance (VUS) are described. Genetic variants were identified in 55.8% of patients, with 16% receiving a definitive molecular diagnosis; 39.8% had VUS. Nine patients were identified with Pompe disease. Conclusions The results demonstrate the effectiveness of this targeted genetic panel and the importance of including Pompe disease in the differential diagnosis for patients presenting with PMW.