Genome Research Division, Human Genetics department, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525KL, Nijmegen, The Netherlands.
Departement of Biology, University of Sistan and Baluchestan, Zahedan, Iran.
Orphanet J Rare Dis. 2019 Feb 13;14(1):41. doi: 10.1186/s13023-018-0981-5.
Bartter Syndrome is a rare, genetically heterogeneous, mainly autosomal recessively inherited condition characterized by hypochloremic hypokalemic metabolic alkalosis. Mutations in several genes encoding for ion channels localizing to the renal tubules including SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, MAGED2 and CASR have been identified as underlying molecular cause. No genetically defined cases have been described in the Iranian population to date. Like for other rare genetic disorders, implementation of Next Generation Sequencing (NGS) technologies has greatly facilitated genetic diagnostics and counseling over the last years. In this study, we describe the clinical, biochemical and genetic characteristics of patients from 15 Iranian families with a clinical diagnosis of Bartter Syndrome.
Age range of patients included in this study was 3 months to 6 years and all patients showed hypokalemic metabolic alkalosis. 3 patients additionally displayed hypercalciuria, with evidence of nephrocalcinosis in one case. Screening by Whole Exome Sequencing (WES) and long range PCR revealed that 12/17 patients (70%) had a deletion of the entire CLCNKB gene that was previously identified as the most common cause of Bartter Syndrome in other populations. 4/17 individuals (approximately 25% of cases) were found to suffer in fact from pseudo-Bartter syndrome resulting from congenital chloride diarrhea due to a novel homozygous mutation in the SLC26A3 gene, Pendred syndrome due to a known homozygous mutation in SLC26A4, Cystic Fibrosis (CF) due to a novel mutation in CFTR and apparent mineralocorticoid excess syndrome due to a novel homozygous loss of function mutation in HSD11B2 gene. 1 case (5%) remained unsolved.
Our findings demonstrate deletion of CLCNKB is the most common cause of Bartter syndrome in Iranian patients and we show that age of onset of clinical symptoms as well as clinical features amongst those patients are variable. Further, using WES we were able to prove that nearly 1/4 patients in fact suffered from Pseudo-Bartter Syndrome, reversing the initial clinical diagnosis with important impact on the subsequent treatment and clinical follow up pathway. Finally, we propose an algorithm for clinical differential diagnosis of Bartter Syndrome.
巴特综合征是一种罕见的、遗传异质性的疾病，主要为常染色体隐性遗传，其特征为低氯低钾代谢性碱中毒。已发现几种位于肾小管的离子通道的基因突变，包括 SLC12A1、KCNJ1、BSND、CLCNKA、CLCNKB、MAGED2 和 CASR，这些基因是导致巴特综合征的潜在分子原因。迄今为止，在伊朗人群中尚未发现具有明确遗传定义的病例。与其他罕见的遗传疾病一样，近年来，下一代测序（NGS）技术的应用极大地促进了遗传诊断和咨询。在这项研究中，我们描述了 15 个伊朗家庭中临床诊断为巴特综合征患者的临床、生化和遗传特征。
本研究纳入的患者年龄范围为 3 个月至 6 岁，所有患者均表现为低钾代谢性碱中毒。3 例患者还伴有高钙尿症，其中 1 例有肾钙质沉着症的证据。全外显子组测序（WES）和长距离 PCR 筛查显示，12/17 例（70%）患者存在 CLCNKB 基因完全缺失，该缺失此前被确定为其他人群中巴特综合征最常见的原因。4/17 例（约 25%的病例）实际上患有假性巴特综合征，其原因是 SLC26A3 基因的新型纯合突变导致先天性氯腹泻，SLC26A4 的已知纯合突变导致 Pendred 综合征，CFTR 的新型突变导致囊性纤维化（CF），以及 HSD11B2 基因的新型纯合功能丧失突变导致明显的盐皮质激素过多综合征。1 例（5%）仍未解决。
我们的研究结果表明，CLCNKB 缺失是伊朗患者巴特综合征的最常见原因，我们还表明，这些患者的临床症状发病年龄以及临床特征存在差异。此外，我们使用 WES 证明，近 1/4 的患者实际上患有假性巴特综合征，这一诊断改变对随后的治疗和临床随访途径具有重要影响。最后，我们提出了巴特综合征的临床鉴别诊断算法。
