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Background: Bartter syndrome is an autosomal recessive salt reabsorption disorder that results in decreased extracellular fluid volume with low/normal blood pressure. Case presentation: A 17-year-old boy with polydipsia, polyuria, weakness in the lower limbs, and ataxic gait. His Laboratory test shows hypokalemia; hypochloremia, hypomagnesemia and metabolic alkalosis. The authors' patient was managed by fluid and electrolyte replacement, which is essential in emergency management. Conclusion: Bartter syndrome is difficult to treat, and currently, there is no complete cure. The overall prognosis depends on the extent of receptor dysfunction, and despite these facts, most patients can live a normal life if they strictly follow their treatment plan.
RESUMEN
Bartter syndrome (BS) is a rare, inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism, hypokalemia, hypochloremia, metabolic alkalosis, and low-to-normal blood pressure. Classic BS, or BS Type 3, the most common subtype in the Asian population, is caused by a molecular defect in ClC-Kb, a voltage-gated chloride channel in renal tubules, due to CLCNKB gene mutation. Because the onset of BS is more common in children than in adults, the diagnosis, treatment outcomes, genotype/phenotype association, and follow-up of adult-onset BS Type 3 are limited. This case report describes the findings in a 20-year-old man who was admitted with hypokalemic paralysis, with clinical manifestations were similar to those of Gitelman syndrome (GS); however, the patient was later diagnosed to have BS Type 3 through genetic testing (NM_000085.4 (CLCNKB): c.1052G>T). A literature review showed that no homozygous mutations have been reported to date. After 5 years of treatment and follow-up, we found that this genotype requires high levels of potassium and is prone to urinary protein and metabolic syndrome. Distinguishing adult-onset BS from GS is challenging in clinical practice. However, genetic diagnosis can help solve this problem effectively, and genotypes play a guiding role in treatment planning.
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Síndrome de Bartter , Canales de Cloruro , Humanos , Masculino , Adulto Joven , Síndrome de Bartter/genética , Síndrome de Bartter/diagnóstico , Síndrome de Bartter/complicaciones , Canales de Cloruro/genética , Estudios de Seguimiento , Síndrome de Gitelman/genética , Síndrome de Gitelman/diagnóstico , Síndrome de Gitelman/complicaciones , MutaciónRESUMEN
BACKGROUND: Long-read sequencing is increasingly used to uncover structural variants in the human genome, both functionally neutral and deleterious. Structural variants occur more frequently in regions with a high homology or repetitive segments, and one rearrangement may predispose to additional events. Bartter syndrome type 3 (BS 3) is a monogenic tubulopathy caused by deleterious variants in the chloride channel gene CLCNKB, a high proportion of these being large gene deletions. Multiplex ligation-dependent probe amplification, the current diagnostic gold standard for this type of mutation, will indicate a simple homozygous gene deletion in biallelic deletion carriers. However, since the phenotypic spectrum of BS 3 is broad even among biallelic deletion carriers, we undertook a more detailed analysis of precise breakpoint regions and genomic structure. METHODS: Structural variants in 32 BS 3 patients from 29 families and one BS4b patient with CLCNKB deletions were investigated using long-read and synthetic long-read sequencing, as well as targeted long-read sequencing approaches. RESULTS: We report a ~3 kb duplication of 3'-UTR CLCNKB material transposed to the corresponding locus of the neighbouring CLCNKA gene, also found on ~50 % of alleles in healthy control individuals. This previously unknown common haplotype is significantly enriched in our cohort of patients with CLCNKB deletions (45 of 51 alleles with haplotype information, 2.2 kb and 3.0 kb transposition taken together, p=9.16×10-9). Breakpoint coordinates for the CLCNKB deletion were identifiable in 28 patients, with three being compound heterozygous. In total, eight different alleles were found, one of them a complex rearrangement with three breakpoint regions. Two patients had different CLCNKA/CLCNKB hybrid genes encoding a predicted CLCNKA/CLCNKB hybrid protein with likely residual function. CONCLUSIONS: The presence of multiple different deletion alleles in our cohort suggests that large CLCNKB gene deletions originated from many independently recurring genomic events clustered in a few hot spots. The uncovered associated sequence transposition haplotype apparently predisposes to these additional events. The spectrum of CLCNKB deletion alleles is broader than expected and likely still incomplete, but represents an obvious candidate for future genotype/phenotype association studies. We suggest a sensitive and cost-efficient approach, consisting of indirect sequence capture and long-read sequencing, to analyse disease-relevant structural variant hotspots in general.
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Síndrome de Bartter , Humanos , Haplotipos , Alelos , Genoma Humano , Canales de Cloruro/genéticaRESUMEN
PURPOSE: Analyze the genotype of 42 Chinese patients with Bartter syndrome type 3 (BS3) and investigate their correlation between genotype and phenotype. METHODS: Identify CLCNKB gene variants by the next-generation sequencing and the multiplex ligation-dependent probe amplification (MLPA), and then evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. RESULTS: Thirty-six different variants in CLCNKB gene, including 13 novel ones, were found. The whole gene deletion of CLCNKB gene was the most frequent mutation (40%), and the rate of large deletions is up to 55%. Among 36 variants, six (c.1244T>A, c.1468G>A, c.849_851delCTT, c.359G>T, c.1052G>T, and c.1309G>A) and three (c.228A>C, c.1294_1295TA>CT, and c.1333T>G) variants were classified as "likely pathogenic variants" and "variants with uncertain significance (VUS)," respectively. The other 27 variants were classified as "pathogenic variants". The most common symptoms included: growth retardation (38/42), polydipsia and polyuria (35/42), constipation (31/42), and vomiting (27/42). All patients presented with hypokalemia, hypochloremia, and metabolic alkalosis. The genotype and phenotype association study revealed that who had mutations probably resulting in complete loss of function of both alleles might have severer phenotype. After the treatment that based on indomethacin and potassium chloride, most patients could achieve obvious recovery of growth rate and restoration of hypokalemia. CONCLUSIONS: The present study have found 36 variants of CLCNKB gene, including 13 novel ones, which enrich the human gene mutation database and provide valuable references to diagnosis, treatment, and the genetic counseling of Chinese population.