Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants
Next-generation sequencing for the diagnosis of MYH9-RD: Predicting pathogenic variants
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DOI：
10.1002/humu.23927
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发表时间：
2019-10-15
期刊：
影响因子：
3.9
通讯作者：
Simeoni, Ilenia
中科院分区：
文献类型：
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作者：
Bury, Loredana;Megy, Karyn;Simeoni, Ilenia
MYH 9相关疾病（MYH 9-RD）的异质性表现，其特征在于巨血小板减少症、白细胞中的Dohle样包涵体、不同严重程度的出血（在某些情况下，累及耳、眼、肾和肝），使得这些患者的诊断在临床实践中仍然具有挑战性。我们收集了3,000多名出血或血小板疾病患者的表型数据并分析了遗传变异。患者入组BRIDGE-BPD和ThromboGenomics项目，并通过高通量测序（HTS）处理其样本。我们确定了50例MYH 9罕见变异的患者。所有患者都有巨血小板，除两名患者外，所有患者都有血小板减少症。50例患者中有41例报告了一定程度的出血素质。11例患者出现听力障碍，3例肾衰竭和2例肝酶升高。在MYH 9中鉴定的28种罕见变异中，有12种是新的。HTS有助于诊断23例患者（46%）。我们的研究结果证实了MYH 9-RD的临床异质性，并表明，在存在未分类的血小板疾病与巨血小板，MYH 9-RD应始终考虑。基于HTS的策略是在临床实践中达到MYH 9-RD的结论性诊断的可靠方法。
The heterogeneous manifestations of MYH9-related disorder (MYH9-RD), characterized by macrothrombocytopenia, Dohle-like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE-BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9-RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9-RD should always be considered. A HTS-based strategy is a reliable method to reach a conclusive diagnosis of MYH9-RD in clinical practice.