Beckwith-Wiedemann综合征(BWS)是一种遗传性疾病,影响全球10,500至13,700名新生儿中的1名。该疾病在绝大多数患者中是由印迹染色体11p15.5的分子缺陷引起的。遗传性球形红细胞增多症(HS)是溶血性贫血的一种形式,与导致先天性红细胞(RBC)膜缺陷的各种突变有关。HS的患病率因世界各地的地理区域而异,从亚洲的100,000人中的1.2到北欧2000年的1人不等。
这里,我们首次报道了一例罕见的BWS和HS并存的病例.基于经典的演讲,包括巨舌,肝脾肿大,巨大儿,该患者首先被怀疑患有BWS。MS-MLPA基于母体11p15.5(KCNQ1OT1)的低甲基化证实了BWS诊断,但CNV-seq未检测到11号染色体的拷贝数变异。然而,仔细检查患者其他症状的分子原因,包括贫血,高胆红素血症,和黄疸,进行全外显子组测序(WES)。我们在ANK1基因(c.520delC)中发现了一个新的从头突变。ANK1基因的这种移码突变导致截短的蛋白质,没有重要的功能域,并且导致红细胞(RBC)的膜稳定性和结构受损。导致明确的HS诊断。
本病例证明多种遗传和表观遗传畸变可能在复杂的遗传疾病中共存。对于这种复杂的案件,不同类型的分子测试,如WES和MS-MLPA,应结合使用以揭示独立的因果分子事件。这项研究的鉴定增加了对共同存在的HS和BWS的分子机制的理解的新见解。
Beckwith-Wiedemann syndrome (BWS) is an inherited disorder affecting 1 in 10,500 to 13,700 newborns worldwide. The disease is caused in a vast majority of patients by a molecular defect in the imprinted chromosome 11p15.5. Hereditary spherocytosis (HS) is a form of hemolytic anemia associated with a variety of mutations leading to congenital red blood cell (RBC) membrane defects. The prevalence of HS varies by geographic regions around the world, ranging from 1.2 in 100,000 in Asia to 1 in 2000 in Northern Europe.
Herein, we report for the first time a rare case diagnosed with co-existing BWS and HS. Based on the classical presentations, including macroglossia, hepatosplenomegaly, and macrosomia, the patient was first suspected with BWS. MS-MLPA confirmed the BWS diagnosis based on hypomethylation of maternal 11p15.5 (KCNQ1OT1), but no copy number variations in chromosome 11 was detected by CNV-seq. Nevertheless, to scrutinize molecular causes of other symptoms of the patient, including anemia, hyperbilirubinemia, and jaundice, a whole exome sequencing (WES) was performed. We identified a novel and de novo mutation in ANK1 gene (c.520delC). This frameshift mutation of ANK1 gene results in a truncated protein without important functional domains and impaired membrane stability and structure of the resultant red blood cells (RBCs), leading to a definitive diagnosis of HS.
The present case demonstrated that multiple genetic and epigenetic aberrations might co-exist in the complex genetic diseases. For such kind of complicated cases, the different types of molecular tests, such as WES and MS-MLPA, should be utilized in combination to reveal independent causal molecular events. The identifications from this study added new insights into the understanding of molecular mechanisms underlying the co-existing HS and BWS.