Perfil genético de doenças renais raras: síndrome de Bartter e síndrome unha-patela

Abstract

Bartter Syndrome (BS) and Nail–Patella Syndrome (NPS) are rare renal genetic diseases. BS affects about 1 in 1,000,000 live births and has autosomal recessive inheritance. It is a tubulopathy, originating from dysfunctions in salt transport in the thick ascending limb of the loop of Henle, located in the nephron. BS is divided into types according to the gene, and consequently the protein, in which the mutation occurs (SLC12A1, KCNJ1, CLCNKB, BSND, or CLCNKA and CLCNKB). The symptoms of BS include salt loss, hypokalemic alkalosis, growth delay, and developmental alterations. Nail Patella Syndrome has an approximate prevalence of 1 in 50,000 live births and has autosomal dominant inheritance. It occurs in people who have pathogenic mutations in the LMX1B gene, which encodes a transcription factor essential to the development of various structures in the embryonic process. Patients may present alterations in the nails, joints, eyes, kidneys, among others. The precise diagnosis of rare genetic diseases is important to guide treatment, provide better genetic counseling to families, and contribute to understanding the physiological processes involved in these pathogeneses. This work is a series of case reports, and aims to identify genetic alterations associated with Bartter and Nail–Patella syndromes in Brazilian patients with clinical suspicion of these conditions. After due consent, molecular diagnosis of the patients and, when possible, their parents was performed. The identified variants were analyzed through consultation of databases and pathogenicity-prediction algorithms to confirm their relation to the patients’ clinical presentation. The study included one NPS patient, with typical clinical manifestations; sequencing revealed the variant rs1588307477 (p.Val265Leu) in the LMX1B gene. Five patients presented BS type III, carrying mutations in the CLCNKB gene, and one of these patients presented a variant not previously reported in the literature (c.1408+1G>C). One patient has BS type IV, with late diagnosis confirmed in this study by the identification of two variants in compound heterozygosity, including the novel variant c.784delG. The contextualization of the presented cases in light of the literature led to the proposal of two hypotheses: that the BSND variant c.139G>A; p.Gly47Arg is associated with a milder phenotypic presentation of type IV SP, and that the BSND variant c.784delG; p.(Ala262Profs*68) has as its pathophysiological mechanism an impairment in the regulation of ClC-K channel transport.