Department of Hematology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
National Institute of Biomedical Genomics, Kalyani, India.
J Mol Diagn. 2020 Apr;22(4):579-590. doi: 10.1016/j.jmoldx.2020.01.007. Epub 2020 Feb 6.
Determination of the cause of inherited hemolysis is based on clinical and stepwise conventional laboratory tests. Patients with obscure etiology require genetic diagnosis, which is time-consuming, expensive, and laborious, mainly because of numerous causal genes. This study enrolled 43 patients with clinical and laboratory evidence of unexplained hemolytic anemia. Initially, 13 patients were tested using a commercial (TruSight One) panel, and remaining cases underwent targeted sequencing using a customized 55-gene panel. Pyruvate kinase deficiency was found in eight, glucose-6-phosphate dehydrogenase (G6PD) deficiency in three (G6PD Guadalajara in two and p.Tyr227Ser: novel, named as G6PD Chandigarh), and glucose-6-phosphate isomerase (GPI) deficiency in two (GPI:p.Arg347His and p.Phe304Leu: novel, named as GPI Chandigarh). Three patients had Mediterranean stomatocytosis/macrothrombocytopenia, and two had overhydrated stomatocytosis. Xerocytosis was found in three patients, whereas six had potentially pathogenic variants in membrane protein-coding genes. Overall, 63% cases received a definite diagnosis. Timely determination of etiology was helpful in diagnosis, genetic counseling, and offering a prenatal diagnosis. Therapeutic implications include performing or avoiding splenectomy that may ameliorate the anemia in many but also predispose to thrombosis in other groups of patients. This first study on the genetic spectrum of unexplained hemolytic anemia from the Indian subcontinent also represents, currently, one of the largest cohort worldwide of such patients.
遗传性溶血性疾病的病因确定基于临床和逐步常规实验室检查。病因不明的患者需要基因诊断，但这种方法耗时、昂贵且费力，主要是因为有许多致病基因。本研究纳入了 43 例具有不明原因溶血性贫血临床和实验室证据的患者。最初，13 例患者使用商业（TruSight One）panel 进行检测，其余病例使用定制的 55 基因 panel 进行靶向测序。8 例患者存在丙酮酸激酶缺乏症，3 例存在葡萄糖-6-磷酸脱氢酶（G6PD）缺乏症（G6PD Guadalajara 2 例，p.Tyr227Ser：新发现，命名为 G6PD Chandigarh），2 例存在葡萄糖-6-磷酸异构酶（GPI）缺乏症（GPI:p.Arg347His 和 p.Phe304Leu：新发现，命名为 GPI Chandigarh）。3 例患者存在地中海口形红细胞增多症/巨血小板减少症，2 例存在过度水化口形红细胞增多症。3 例患者存在先天性非球形细胞溶血性贫血，6 例患者存在膜蛋白编码基因的潜在致病性变异。总体而言，63%的病例获得了明确诊断。及时确定病因有助于诊断、遗传咨询和提供产前诊断。治疗意义包括进行或避免脾切除术，这可能改善许多患者的贫血，但也使其他患者易发生血栓形成。这项来自印度次大陆的不明原因溶血性贫血遗传谱的首次研究，目前也是全球此类患者最大的队列之一。
