Gorka Fernández-Eulate, Julian Theuriet, Christopher J Record, Giorgia Querin, Marion Masingue, Sarah Leonard-Louis, Anthony Behin, Nadine Le Forestier, Antoine Pegat, Maud Michaud, Jean-Baptiste Chanson, Aleksandra Nadaj-Pakleza, Celine Tard, Anne-Laure Bedat-Millet, Guilhem Sole, Marco Spinazzi, Emmanuelle Salort-Campana, Andoni Echaniz-Laguna, Vianney Poinsignon, Philippe Latour, Mary M Reilly, Francoise Bouhour, Tanya Stojkovic
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The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders.</p><p><strong>Methods: </strong>Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel.</p><p><strong>Results: </strong>Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: <i>BICD2</i> (n = 9), <i>DYNC1H1</i> (n = 7), <i>TRPV4</i> (n = 4), <i>VCP</i>, <i>HSBP1</i>, <i>AR</i> (n = 2), <i>VRK1</i>, <i>DNAJB2</i>, <i>MORC2</i>, <i>ASAH1</i>, <i>HEXB</i>, and unexpectedly, <i>COL6A3</i> (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS.</p><p><strong>Discussion: </strong>Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. 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引用次数: 0
摘要
背景和目的：脊髓性肌萎缩症（SMA）主要由5q13上的同卵SMN1基因缺失引起。非5q SMA患者序列缺乏，下一代测序（NGS）的诊断率在很大程度上是未知的。本研究旨在描述非 5q SMA 的临床和遗传情况，并评估神经病变基因面板在这些疾病中的表现：方法：描述在法国和英国伦敦不同神经肌肉参考中心随访的非 5q SMA 患者。未经基因诊断的患者至少已接受神经病变或大神经肌肉基因检测：结果：共纳入了来自 65 个不同家族的 71 名患者，其中大部分为散发性病例（60.6%）。发病时，21 名患者（29.6%）表现为近端无力（P-SMA），35 名患者（49.3%）表现为相关的远端无力（PD-SMA），15 名患者（21.1%）表现为肩胛骨表型（SP-SMA）。32 名患者（45.1%）得到了基因诊断：BICD2（9 人）、DYNC1H1（7 人）、TRPV4（4 人）、VCP、HSBP1、AR（2 人）、VRK1、DNAJB2、MORC2、ASAH1、HEXB，以及意外的 COL6A3（1 人）。与PD-SMA（16/35，45.7%）和SP-SMA（10/15，66.7%）相比，P-SMA的基因诊断率最低（6/21，28.6%）。较早发病、有家族病史或近亲结婚是基因诊断阳性的独立预测因素。对59名患者进行了神经病变基因检测，诊断率为32.2%（19/59）。另有 13 名患者通过单个基因测序或其他神经肌肉 NGS 获得了基因诊断：讨论：非 5q SMA 具有遗传异质性，神经病变基因检测可对三分之一的患者进行分子诊断。对其他神经肌肉和神经代谢基因进行测序可提高诊断率。尽管如此，对这些患者进行分组以帮助鉴定新基因的需求仍未得到满足。
Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy.
Background and objectives: Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders.
Methods: Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel.
Results: Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: BICD2 (n = 9), DYNC1H1 (n = 7), TRPV4 (n = 4), VCP, HSBP1, AR (n = 2), VRK1, DNAJB2, MORC2, ASAH1, HEXB, and unexpectedly, COL6A3 (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS.
Discussion: Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes.
期刊介绍：
Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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