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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; Kordi-Tamandani, DM; Behjati, F; Sadeghi-Bojd, S; Bakey, Z; Karimiani, EG; Schüle, I; Azarfar, A; 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 J Rare Dis, 14 (1). p. 41. ISSN 1750-1172 https://doi.org/10.1186/s13023-018-0981-5
SGUL Authors: Karimiani, Ehsan Ghayoor

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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.

Item Type: Article
Additional Information: © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Bartter syndrome, Pseudo-Bartter-syndrome, Whole exome sequencing, 11-beta-Hydroxysteroid Dehydrogenase Type 2, Algorithms, Bartter Syndrome, Child, Child, Preschool, Chloride Channels, Chloride-Bicarbonate Antiporters, Diagnosis, Differential, Female, Humans, Infant, Iran, Male, Sulfate Transporters, Whole Exome Sequencing, Humans, Bartter Syndrome, 11-beta-Hydroxysteroid Dehydrogenase Type 2, Chloride Channels, Chloride-Bicarbonate Antiporters, Diagnosis, Differential, Algorithms, Child, Child, Preschool, Infant, Iran, Female, Male, Whole Exome Sequencing, Sulfate Transporters, Bartter syndrome, Whole exome sequencing, Pseudo-Bartter-syndrome, 1199 Other Medical And Health Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Orphanet J Rare Dis
ISSN: 1750-1172
Language: eng
Dates:
DateEvent
13 February 2019Published
14 December 2018Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
716344European Research Councilhttp://dx.doi.org/10.13039/501100000781
CRC1140_KIDGEMDeutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659
PubMed ID: 30760291
Web of Science ID: WOS:000458673900004
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/111220
Publisher's version: https://doi.org/10.1186/s13023-018-0981-5

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