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Orphanet J Rare Dis. 2019 Feb 13;14(1):41. doi: 10.1186/s13023-018-0981-5.

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.

Author information

1
Genome Research Division, Human Genetics department, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525KL, Nijmegen, The Netherlands.
2
Departement of Biology, University of Sistan and Baluchestan, Zahedan, Iran.
3
Departement of Biology, University of Sistan and Baluchestan, Zahedan, Iran. dor_kordi@yahoo.com.
4
Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
5
Children and Adolescents Health Research Center, resistant tuberculosis institute, Zahedan University of Medical Sciences, Zahedan, Iran.
6
Center for Pediatrics and Adolescent Medicine, Freiburg University Hospital, Freiburg University Faculty of Medicine, Mathildenstrasse 1, 79112, Freiburg, Germany.
7
Razavi Cancer Research, Razavi Hospital, Imam Reza International University, Mashhad, Iran.
8
Next Generation Genetic Polyclinic, Mashhad, Iran.
9
Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
10
Genome Research Division, Human Genetics department, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525KL, Nijmegen, The Netherlands. miriam.schmidts@uniklinik-freiburg.de.
11
Center for Pediatrics and Adolescent Medicine, Freiburg University Hospital, Freiburg University Faculty of Medicine, Mathildenstrasse 1, 79112, Freiburg, Germany. miriam.schmidts@uniklinik-freiburg.de.
12
Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, 79112, Freiburg, Germany. miriam.schmidts@uniklinik-freiburg.de.

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.

KEYWORDS:

Bartter syndrome; Pseudo-Bartter-syndrome; Whole exome sequencing

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