Two different pathogenic gene mutations coexisted in the same hereditary spherocytosis family manifested with heterogeneous phenotypes
Two different pathogenic gene mutations coexisted in the same hereditary spherocytosis family manifested with heterogeneous phenotypes
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DOI：
10.1186/s12881-019-0826-7
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发表时间：
2019-05-24
影响因子：
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通讯作者：
Shi, Xiaoliu
中科院分区：
文献类型：
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作者：
Shen, Hongwei;Huang, Hui;Shi, Xiaoliu
背景遗传性球形细胞增多症(HS)是一种常见的遗传性溶血性贫血。根据目前的HS诊断标准，有HS家族史、典型临床特征和实验室检查的患者无需进行任何额外的测试，包括基因分析，即可诊断出HS。然而，临床上的异质性给HS的诊断带来了困难。因此，我们旨在探讨基因诊断在家族性队列中的应用。病例介绍在目前的中国家庭中，两个先证者具有相似的临床表现，包括黄疸、胆石症、脾肿大和球状细胞，而其他家庭成员的临床特征尚不确定。全外显子组测序(WES)出人意料地在这两个先证者中发现了两个独立的致病突变。先证者D中发现的SPTB R1625X突变是一种新生突变；先证者W从母亲那里遗传了SLC4A1 c.G1469A突变，而她的兄弟也遗传了SLC4A1 c.G1469A突变。但先证者W与其母亲、兄弟的临床特征不同：先证者W有明显的脾肿大、黄胆和胆结石，需行胆囊切除和脾切除，而其母亲和兄弟的HS不合并胆石症，其脾肿大和血清胆红素水平中等。此外，在该家系中未发现与HS相关症状相关的其他基因组缺陷。结论同一HS家系中的两种基因型和表型可能是不同的。致病基因突变分析可能在HS患者及其家庭成员的准确诊断和遗传咨询中发挥不可或缺的作用。
BackgroundHereditary spherocytosis (HS) is a common type of hereditary hemolytic anemia. According to the current diagnostic criteria of HS, patients with a family history of HS, typical clinical features and laboratory investigations could be diagnosed without the requirement of any additional tests, including genetic analysis. However, the clinical heterogeneities incur difficulties in HS diagnosis. We therefore aimed to investigate the application of genetic diagnosis in a family-based cohort.Case presentationIn the present Chinese family, two probands sharing similar clinical manifestations, including jaundice, cholelithiasis, splenomegaly and spherocytes, while the clinical features of other family members were inconclusive. Whole-exome sequencing (WES) unexpectedly unveiled two separate disease-causing mutations in the two probands. SPTB R1625X mutation detected in proband D was a de novo mutation; while proband W inherited the SLC4A1 c.G1469A mutation from her mother, which was also inherited by her brother. However, the clinical features of proband W and her mother and brother were discrepant: proband W suffered from significant splenomegaly, jaundice and cholelithiasis, which resulted in cholecystectomy and splenectomy; while her mother and brother's HS were not complicated by cholelithiasis, and their splenomegaly and elevated serum bilirubin were moderate. In addition, additional genomic defects involved with HS-related symptoms have not been detected in this family.ConclusionsBoth genotypes and phenotypes could be heterogeneous in the same HS family. The analysis of pathogenic gene mutations may endeavor to play an indispensable role in the accurate diagnosis and genetic consultation of HS individuals and their family members.