Mimicry and well known genetic friends: Molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis

Najafi, M. and Kordi-Tamandani, D. M. and Behjati, F. and Sadeghi-Bojd, S. and Bakey, Z. and Karimiani, E. G. and Schüle, I. and Azarfar, A. and Schmidts, M. (2019) Mimicry and well known genetic friends: Molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis. Orphanet Journal of Rare Diseases, 14 (1).

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Abstract

Background: 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. Results: 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. Conclusions: 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. © 2019 The Author(s).

Item Type: Article
Additional Information: Cited By :1 Export Date: 16 February 2020 Correspondence Address: Kordi-Tamandani, D.M.; Departement of Biology, University of Sistan and BaluchestanIran; email: dorkordi@yahoo.com
Uncontrolled Keywords: Bartter syndrome Pseudo-Bartter-syndrome Whole exome sequencing 11beta hydroxysteroid dehydrogenase 2 cystic fibrosis transmembrane conductance regulator pendrin bicarbonate chloride antiporter chloride channel CLCNKB protein, human HSD11B2 protein, human SLC26A3 protein, human SLC26A4 protein, human apparent mineralocorticoid excess syndrome Article CFTR gene child chloride diarrhea CLCNKB gene clinical article cohort analysis cystic fibrosis differential diagnosis female gene HSD11B2 gene human hypercalciuria hypokalemic alkalosis infant Iran kidney calcification male molecular diagnosis Pendred syndrome polymerase chain reaction practice guideline preschool child pseudo Bartter syndrome SLC26A3 gene SLC26A4 gene algorithm genetics procedures 11-beta-Hydroxysteroid Dehydrogenase Type 2 Algorithms Child, Preschool Chloride Channels Chloride-Bicarbonate Antiporters Diagnosis, Differential Humans Sulfate Transporters
Subjects: QZ pathology-neoplasms-Genetics
Divisions: Mashhad University of Medical Sciences
Depositing User: mr lib1 lib1
Date Deposited: 21 Jun 2020 09:26
Last Modified: 21 Jun 2020 09:26
URI: http://eprints.mums.ac.ir/id/eprint/18558

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