A Novel Homozygous Variant Of The SLC12A3 Gene In Gitelman Syndrome Pedigree And Literatu Rereview

Background:Gitelman syndrome(GS),an autosomal recessive disorder,is characterized by hypokalemic alkalosis combined with hypomagnesemia,hypocalciuria,and increased renin activity associated with low or normal-low blood pressure.GS is caused by mutations in solute carrier family 12 member 3(SLC12A3)gene,which encodes the thiazide-sensitive NaCl cotransporter(NCCT)of the distal convoluted tubule(DCT).The clinical manifestations of GS are variable,In clinical practice,it is sometimes difficult to distinguish GS from Bartter syndrome,which requires further genetic determination for diagnosis.In this study,we reported a case of GS pedigree and reviewed literature so as to explore the relationship between phenotype and genotype,and provide a reference for clinical diagnosis and treatment.Methods:A 14-year-old Chinese male was referred to the First Affiliated Hospital of Nanchang University for repeated bilateral lower limb weakness for more than 10 years and aggravation for two months.General clinical data of the patients were collected,and blood electrolyte,renin-angiotensin-aldosterone,blood gas analysis,renal color doppler ultrasound and electrocardiogram were performed.Direct sequencing was performed on the pathogenic target genes SLC12A3,SLC12A1,KCNJ1,CLCNKB,BSND,CLCNKA and CASR of Gitelman syndrome and Bartter syndrome to find the pathogenic mutation locus.Functional analysis of mutation sites was performed by online gene function analysis software.Result:The patient had severe hypokalemia,hypomagnesemia,hypocalciuria,hypochl-oric metabolic alkalosis,increased renin activity,lower glomerular filtration rate(GFR),mild proteinuria and thyroid dysfunction.Blood pressure was normal during hospitalization.Genetic tests with the patient found a novel homozygous mutation of SLC12A3 gene(c.1948 G > A,p.Gly650Arg)in exon 16 and a heterozygous mutation of CLCNKB gene(c.1039 T > A,p.Phe347Ile)in exon 11.His mother and elder brother were diagnosed as heterozygous carriers of the two genes,the father only carried the SLC12A3 mutation.The family members had no clinical symptoms.Conclusions:The clinical symptoms and laboratory results of the patient were consistent with GS manifestations,and the homozygous mutation of SLC12A3 gene accords with autosomal recessive inheritance,So it is clear to diagnose Gitelman syndrome.At the same time,this study also explores the relationship between Gitelman syndrome and renal function,thyroid function.Since the phenotype of Gitelman syndrome is highly heterogeneous and the relationship between genotype and phenotype is not clear,the exact diagnosis of clinically suspected Gitelman syndrome patients requires further genetic testing to achieve early diagnosis,formulate treatment plans and prevent the occurrence of complications.