BackgroundGitelman syndrome is a salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers.MethodsTo evaluate the phenotype of heterozygous carriers of pathogenic SLC12A3 mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test.ResultsWe enrolled 242 participants, aged 18–75 years, including 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome. The three groups had similar age, sex ratio, and body mass index. Compared with healthy noncarriers, heterozygous carriers showed significantly higher serum calcium concentration (P=0.01) and a trend for higher plasma aldosterone (P=0.06), but measures of home BP, plasma and urine electrolytes, renin, parathyroid hormone, vitamin D, and response to oral glucose tolerance testing were similar. Patients with Gitelman syndrome had lower systolic BP and higher heart rate than noncarriers and heterozygote carriers; they also had significantly higher fasting serum glucose concentration, higher levels of markers of insulin resistance, and a three-fold higher sensitivity to overweight. According to oral glucose tolerance testing, approximately 14% of patients with Gitelman syndrome were prediabetic, compared with 5% of heterozygous carriers and 4% of healthy noncarriers.ConclusionsHeterozygous carriers had a weak intermediate phenotype, between that of healthy noncarriers and patients with Gitelman syndrome. Moreover, the latter are at risk for development of type 2 diabetes, indicating the heightened importance of body weight control in these patients.

Using a SNP-based linkage approach, 7 suggestive linkage regions (maximum logarithm of odds [LOD] score = 1.8 in all linked regions) were identified in this panel (Supplemental Table 1B). In total, linked regions spanned 69 Mb and included 829 protein-coding genes. After filtering, WES performed in 1 unaffected and 2 affected individuals identified 71 possible disease-causing coding variants (Supplemental Table 1C). Four missense variants mapped to the linkage regions and were predicted in silico to be damaging. These variants were located in solute carrier family 30 member 7, a zinc transporter (SLC30A7), kinesin family member 11 (KIF11), tectonic family member 3 (TCTN3), and WNK1. The WNK1 variant (c.1905T>A; P.Asp635Glu) (Figure 1B) was located in exon 7 (ex7), which encodes the conserved acidic motif, previously shown to mediate the interaction with the substrate adaptor KLHL3 ( 14).Additional variants in the WNK1 acidic motif in other cases and kindreds. FHHt-causing WNK4 mutations are located in ex7 and ex17, encoding highly conserved acid and base motifs, respectively. Thus, we screened the homologous motifs of WNK1 encoded by ex7 and ex25, respectively, in 26 unrelated affected cases previously found as negative for the classical mutations in WNK4, KLHL3, CUL3, or the intron 1 deletion in WNK1. Direct sequencing identified 5 additional nonsynonymous heterozygous variants in ex7 in 8 unrelated subjects (Figure 2, A-C). The in silico pathogenicity of these variants is described in Supplemental Table 2. All were located within the acidic motif, between positions 631 and 636 of the L-WNK1 protein, and were predicted to be pathogenic. Four of the 6 missense variants were charge changing (E631K, D635N, Q636R, Q636E); 2 affected residues (D635, Q636) were also found mutated in the homologous acidic motif of WNK4 (D564 and Q565, Figure 2, C and D)Clinical and biochemical characteristics: hydrochlorothiazide-sensitive hyperkalemic acidosis without hypertension. Detailed clinical and biological characteristics of index cases are given in Table 1. The circumstances of discovery and the clinical symptoms of these index patients are detailed in Supplemental Table 3. In most of the cases, patients were asymptomatic and showed with no signs of hyperkalemia on an electrocardiogram. All displayed the electrolyte anomalies typical of FHHt, including marked hyperkalemia (median, 5.9 mmol/L; IQR, 5.3-6.3), hyperchloremia (median, 108 mmol/L; IQR, 106-110), and metabolic acidosis (total CO 2 , 20 mmol/L; IQR, 19-21) despite a normal glomerular filtration rate (GFR) (median creatinine, 58 μmol/L; IQR, 47-74). For the 7 index cases with prospective reliable clinical data, hyperkalemia and hyperchloremia were rapidly corrected with low doses of hydrochlorothiazide (HCTZ) (6.25 to 25 mg/d; Supplemental Figure 1). In comparison, an average drop in potassium of only 0.7 mmol/L was observed in normal, healthy subjects administered a much higher dose of HCTZ (50 mg for 3 weeks) (15). Compared with reference values (16), we also obser...

Background: Gitelman syndrome (GS) is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. GS is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of GS, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a GS phenotype, the genotype is unknown. Methods: We identified mitochondrial DNA (mtDNA) variants in three families with GS-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced In NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. Results: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF) and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV reduced maximal mitochondrial respiratory capacity in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Conclusion: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a GS-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained GS-like tubulopathies.

I nherited renal tubulopathies are rare diseases often diagnosed in children, particularly those with autosomal recessive transmission. Although some tubulopathies are diagnosed in adulthood, including recessive diseases with potentially mild presentation (e.g., Gitelman syndrome), slowly progressive dominant diseases (e.g., autosomal dominant tubulointerstitial kidney disease), and diseases with variable severity (e.g., Dent disease), the prevalence of tubulopathies in adults remains mostly unknown. 1-3 In addition, the clinical presentation may be atypical or insidious, complicating and delaying the diagnosis of tubular dysfunction. 4 Advances in understanding renal tubular solute transport systems has been achieved through the elucidation of

Objective: Neural tube defects (NTDs) are one of the most common congenital anomalies caused by a complex interaction of many genetic and environmental factors. In about 10% of cases, NTDs are associated with genetic syndromes or chromosomal anomalies. Among these, SOX3 duplication has been reported in some isolated cases. The phenotype associated with this microduplication is variable and includes myelomeningocele (MMC) in both sexes as well as hypopituitarism and cognitive impairment in males. In order to determine the prevalence of this anomaly in fetuses with MMC, a retrospective cohort of fetuses with MMC was analyzed by quantitative PCR (qPCR) targeting SOX3 locus. Methods:The detection of an SOX3 microduplication by chromosomal microarray analysis (CMA) in two female fetuses with MMC prompted us to analyze retrospectively by qPCR this gene in a cohort of 53 fetuses with MMC.Results: In addition to our two initial cases, one fetus harboring an Xq27.1q28 duplication that encompasses the SOX3 gene was detected.Conclusion: Our data demonstrate that SOX3 duplication is a genomic imbalance involved in the pathogenesis of NTDs. In addition, our survey highlights the importance of CMA testing in fetuses with NTDs to enable genetic counseling upstream of any considerations of in utero fetal surgery.

Nephrocalcinosis due to infantile hypercalcemia can be a cause of fetal hyperechogenic kidneys, which suggests early antenatal anomaly of calcium and phosphate metabolism. This entity should be considered in differential diagnosis. Postnatal follow-up of infants with hyperechogenic kidneys should include evaluation of calcium and phosphate metabolism.

Objectives Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD. Methods In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015. Results A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n = 10), 22q11.21 duplications (n = 2), 8p23 deletions (n = 2), an Alagille syndrome (n = 1), and a Kleefstra syndrome (n = 1). Conclusion The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions.

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