Search

Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular transport of magnesium is mandatory for magnesium homeostasis. In addition to intestinal absorption that occurs in part across the paracellular pathway, magnesium is reabsorbed by the kidney tubule. The bulk of magnesium is reabsorbed through the paracellular pathway in the proximal tubule and the thick ascending limb of the loop of Henle. The finding that rare genetic diseases due to pathogenic variants in genes encoding specific claudins (CLDNs), proteins located at the tight junction that determine the selectivity and the permeability of the paracellular pathway, led to an awareness of their importance in magnesium homeostasis. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused by a loss of function of CLDN16 or CLDN19. Pathogenic CLDN10 variants cause HELIX syndrome, which is associated with a severe renal loss of sodium chloride and hypermagnesemia. The present review summarizes the current knowledge of the mechanisms and factors involved in paracellular magnesium permeability. The review also highlights some of the unresolved questions that need to be addressed.

Introduction Familial hyperkalemic hypertension is a rare inherited form of arterial hypertension. Four genes are responsible for this disease, the variants of these genes cause disruption in the regulation of ion transport in the distal renal tubule. Whether the genotype explains the large phenotypic heterogeneity has not been fully explored. Methods We retrospectively analyzed clinical and genetic data of 153 cases (84 probands, 69 relatives) with familial hyperkalemic hypertension. Results Pathogenic variants (25 novel variants) were identified as follows: KLHL3 (n = 50), CUL3 (n = 16), WNK1 acidic motif (n = 11), WNK4 acidic motif (n = 4) and WNK1 intron 1 deletions (n = 3). De novo cases were mainly observed in the CUL3-related cases (9 of 12) and recessive cases were only observed in KLHL3-related cases (14 of 50). More severe forms were observed in recessive KLHL3 and CUL3 cases that were also associated with growth retardation. Patients with WNK1 acidic motif variants had a typical biological phenotype and lower frequency of hypertension conversely to WNK4 variants affecting the same motif. Patients with heterozygous KLHL3 and WNK1 deletions had milder forms. Familial screening in 178 relatives allowed detection and care for 69 positive cases. Blood pressure and hyperkalemia were improved by hydrochlorothiazide in all groups. Conclusions This study confirms the phenotypic variability ranging from the severe and early forms associated with CUL3 and recessive KLHL3 genotypes through intermediate forms associated with KLHL3 dominant, WNK4 and WNK1 deletion to mild form associated with WNK1 acidic motif genotype and reinforces the interest of genetic screening to better orientate medical care and genetic counseling., Graphical abstract

Biallelic pathogenic variants in the SLC34A3 gene, encoding for the NPT2c cotransporter, cause Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH). However, the associated phenotype is highly variable. In addition, mice deleted for Slc34a3 exhibit a different phenotype compared to humans, without urinary phosphate leakage. The mechanisms by which SLC34A3 variants disrupt phosphate/calcium metabolism are un-completely understood. In this study we explored these mechanisms in vitro using SLC34A3 variants identified in patients with urinary phosphate leakage. We analyzed the consequences of these variants on NPT2c function and the link with the phenotype of the patients. We studied 20 patients with recurrent nephrolithiasis and low serum phosphate concentration harboring variants in the SLC34A3 gene. Half of the patients carried homozygous or composite heterozygous variants. Three patients had in addition variants in SLC34A1 and SLC9A3R1 genes. All these patients benefited from a precise analysis of their phenotype. We generated 13 of these mutants by site-directed mutagenesis. Then we carried out transient transfections of these mutants in HEK cells and measured their phosphate uptake capacity under different conditions. Among the 20 patients included, 3 had not only mutations in NPT2c but also in NPT2a or NHERF1 genes. Phosphate uptake was decreased in 8 NPT2c mutants studied and normal for 5. Four variants were initially categorized as variants of uncertain significance. Expression of the corresponding mutants showed that one did not modify phosphate transport, two reduced it moderately and one abolished it. Co-transfection of the NPT2c mutants with the wild-type plasmid of NPT2c or NPT2a did not reveal dominant negative effect of the mutants on NPT2c-mediated phosphate transport. A detailed analysis of patient phenotypes did not find a link between the severity of the disorder and the level of phosphate transport impairment. NPT2c mutations classified as ACMG3 identified in patients with renal phosphate leak should be characterized by in vitro study to check if they alter NPT2c-mediated phosphate transport since phosphate uptake capacity may not be affected. In addition, research for mutations in NHERF1 and NPT2a genes should always be associated to NPT2c sequencing.

Prenatal diagnosis of bone and mineralization anomalies is associated with a wide range of etiologies and prognoses. The improvement of antenatal ultrasound combined with the development of molecular diagnosis in genetics has transformed antenatal medicine into a challenging discipline. Of the various known causes of bone abnormalities and hypomineralization, calcium and phosphate metabolism disorders are exceptional. An accurate diagnosis is crucial for providing appropriate genetic counseling and medical follow-up after birth.We report on three siblings with severe bone abnormalities diagnosed during the second trimester ultrasound of pregnancy. Postnatal follow-up showed transitory hyperparathyroidism, with hypercalcemia and hypocalciuria.Sanger sequencing performed after birth in the three newborns revealed a monoallelic pathogenic variant in the CASR gene, encoding the calcium sensing receptor, confirming the diagnosis of familial hypocalciuric hypercalcemia, paternally inherited. Postnatal evolution was favorable after treatment with a calcimimetic agent.Previously, prenatal bone abnormalities caused by familial hypocalciuric hypercalcemia had only been described in one patient. This entity should be considered as differential diagnosis of bones abnormalities. Knowing about this unusual etiology is important to guide the diagnosis, the prenatal counseling and to improve medical management.

International audience; ObjectiveFamilial hypocalciuric hypercalcaemia type 1 (FHH1), related to heterozygous loss‐of‐function mutations of the calcium‐sensing receptor gene, is the main differential diagnosis for primary hyperparathyroidism. The aim of our study was to describe clinical characteristics of adult patients living in France with a genetically confirmed FHH1.Design and patientsThis observational, retrospective, multicentre study included 77 adults, followed up in 32 clinical departments in France, with a genetic FHH1 diagnosis between 2001 and 2012.ResultsHypercalcaemia was diagnosed at a median age of 53 years [IQR: 38‐61]. The diagnosis was made after clinical manifestations, routine analysis or familial screening in 56, 34 and 10% of cases, respectively, (n = 58; data not available for 19 patients). Chondrocalcinosis was present in 11/51 patients (22%), bone fractures in 8/56 (14%) and renal colic in 6/55 (11%). The median serum calcium was 2.74 mmol/L [IQR: 2.63‐2.86 mmol/L], the median plasma parathyroid hormone level was 4.9 pmol/L [3.1‐7.1], and the median 24‐hour urinary calcium excretion was 2.8 mmol/24 hours [IQR: 1.9‐4.0]. Osteoporosis (dual X‐ray absorptiometry) or kidney stones (renal ultrasonography) were found in 6/38 patients (16%) and 9/32 patients (28%), respectively. Fourteen patients (18%) underwent parathyroid surgery; parathyroid adenoma was found in three patients (21%) and parathyroid hyperplasia in nine patients (64%). No correlation between genotype and phenotype was established.ConclusionThis large cohort study demonstrates that FHH1 clinical characteristics can be atypical in 33 patients (43%). Clinicians should be aware of this rare differential diagnosis in order to adopt an appropriate treatment strategy.

Contains fulltext : 248375.pdf (Publisher’s version ) (Closed access) BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome 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 Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-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 (22)Na(+) 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 and reduced maximal mitochondrial respiratory capacity were found 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 Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.

Nephrogenic diabetes insipidus is defined as an inability to concentrate urine due to a complete or partial alteration of the renal tubular response to arginine vasopressin hormone, resulting in excessive diluted urine excretion. Hereditary forms are caused by molecular defects in the genes encoding either of the two main renal effectors of the arginine vasopressin pathway: the AVPR2 gene, which encodes for the type 2 vasopressin receptor, or the AQP2 gene, which encodes for the water channel aquaporin-2. About 90% of cases of nephrogenic diabetes insipidus result from loss-of-function variants in the AVPR2 gene, which are inherited in a X-linked recessive manner. The remaining 10% of cases result from loss-of-function variants in the AQP2 gene, which can be inherited in either a recessive or a dominant manner. The main symptoms of the disease are polyuria, chronic dehydration and hypernatremia. These symptoms usually occur in the first year of life, although some patients present later. Diagnosis is based on abnormal response in urinary osmolality after water restriction and/or administration of exogenous vasopressin. Treatment involves ensuring adequate water intake on demand, possibly combined with thiazide diuretics, non-steroidal anti-inflammatory drugs, and a low-salt and protein diet. In this review, we provide an update on current understanding of the molecular basis of inherited nephrogenic insipidus diabetes.

Background: Genetic analyses have experienced rapid development over the past decades. This evolution is accompanied by a considerable increase in indications in clinical practice. As a result, physicians are exposed to prescribing and understanding genetics results in their daily practice. The objective was to assess the knowledge of young physicians on new genetic techniques and their expectations concerning molecular biology education. Methods: This study is based on the results of an anonymized questionnaire on genetics knowledge sent to young French physicians specialized in medical oncology, radiation therapy, and clinical hematology in France; and on a retrospective analysis of nonconformities to requirements of the ISO 15189 accreditation standard in genetics samples from a Parisian university hospital center. Results: Of the 87 young physicians (median age 29, 58.6% female) who responded to the survey, 60.3% did not differentiate several standard molecular biology techniques. Median Visual Analog Scale for theoretical knowledge of standard genetic technics was 35/100 (IQR 20-56). Median Visual Analogical Scale for genetics diagnostic and theragnostic indications knowledge were 50/100 (IQR 31.2-70) and 43/100 (IQR 19.2-65), respectively. Proficiency in genetics results interpretation was assessed with a Median Visual Analog Scale of 47/100 (IQR 23.25-69). Finally, 82.4% of young physicians believed that the current teaching of molecular biology was not suited to their current practice and 91.9% requested a specific training implementation. These results were supported by the high rate of nonconformities regarding the prescription (43%) among the different types of nonconformities of genetics samples.Conclusion: Medical education on new techniques of genetics by young French physicians appears to be insufficient, and a specific training should be considered. A better knowledge of this discipline is necessary in order to control the clinical, ethical and financial issues associated with the exponential use of molecular biology in medicine.

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.

International audience; Mutations in the CLCN5 gene encoding the 2Cl- /1H+ exchanger ClC-5 are associated with Dent disease 1, an inherited renal disorder characterized by low molecular weight (LMW) proteinuria and hypercalciuria. In the kidney, ClC-5 is mostly localized in proximal tubule cells where it is thought to play a key role in the endocytosis of LMW proteins. Here, we investigated the consequences of eight previously reported pathogenic missense mutations of ClC-5 surrounding the "proton glutamate" that serves as a crucial H+ -binding site for the exchanger. A complete loss of function was observed for a group of mutants that were either retained in the endoplasmic reticulum of HEK293T cells or unstainable at plasma membrane due to proteasomal degradation. In contrast, the currents measured for a second group of mutations in X. laevis oocytes were reduced. Molecular Dynamics simulations performed on a ClC-5 homology model demonstrated that such mutations may alter ClC-5 protonation by interfering with the water pathway. Analysis of clinical data from patients harboring these mutations demonstrated no phenotype/genotype correlation. This study reveals that mutations clustered in a crucial region of ClC-5 have diverse molecular consequences in patients with Dent disease 1, ranging from altered expression to defects in transport. This article is protected by copyright. All rights reserved.

Purpose Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. Methods First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. Results 6.4% of ABCC6-negative PXE patients (n=3) harbored biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. Conclusion CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

Hypokalemia and metabolic alkalosis can be present in different rare diseases, and the differential diagnosis of these forms is challenging. Apparent mineralcorticoid (AME) excess syndrome is one of these conditions. Characterized by increased blood pressure due to excessive sodium retention and plasma volume, it is caused by a mutation in the HSD11B2 gene encoding the oxydoreductase enzyme 11β-hydroxysteroide dehydrogenase type 2. We report the case of a child presenting with failure to thrive associated with early detection of hypokalemia, metabolic alkalosis, nephrocalcinosis and hypertension in which AME syndrome was detected. A novel mutation in the HSD11B2 gene was identified in this patient. In clinical pictures characterized by metabolic alkalosis and hypokalemia, the evaluation of renin, aldosterone and blood pressure is crucial for accurate diagnosis. AME syndrome is a rare disorder that can be an insidious but lethal disease, if untreated. With clinical signs appearing during the first days of life. Early diagnosis is imperative in order to enable prompt and adequate treatment to improve the outcome of these patients.

Renal pseudohypoaldosteronism (PHA1) is a mild form of an aldosterone-resistance syndrome caused by mutations in the NR3C2 gene that codes for the mineralocorticoid receptor (MR). The disease is inherited as an autosomal dominant trait characterized by signs and symptoms of salt-losing in infancy. Disease manifestations could be severe in infancy but improve after the age of 1-3 years. Some affected members are asymptomatic and remain so life-long. In this study, we report the identification of a large deletion in the NR3C2 gene (c.1897+1_1898-1)_(c.*2955+?)del in renal PHA1 patients from an extended family spanning four generations. We prospectively evaluated the plasma renin activity and serum aldosterone profiles over four decades in symptomatic and asymptomatic affected family members. The benefits of early diagnosis on the clinical outcome were assessed as well. The long-term follow-up showed an age-dependent decrease in both plasma renin activity and serum aldosterone levels over the years. However, aldosterone levels remain high life-long. Thus, levels of aldosterone are a reliable marker to detect asymptomatic family members. The diagnosis of the proposita led to early diagnosis and therapy in other affected family members, significantly mitigating the clinical course. Despite the extremely elevated serum aldosterone levels during pregnancy, affected pregnant women did not experience any ill effects. However, this should be verified by observations in other adult patients.

International audience; Hereditary tubulopathies are rare diseases with unknown prevalence in adults. Often diagnosed in childhood, hereditary tubulopathies can nevertheless be evoked in adults. Precise diagnosis can be difficult or delayed due to insidious development of symptoms, comorbidities and polypharmacy. Here we evaluated the diagnostic value of a specific panel of known genes implicated in tubulopathies in adult patients and compared to our data obtained in children. To do this we analyzed 1033 non-related adult patients of which 744 had a clinical diagnosis of tubulopathy and 289 had a diagnosis of familial hypercalcemia with hypocalciuria recruited by three European reference centers. Three-quarters of our tubulopathies cohort included individuals with clinical suspicion of Gitelman syndrome, kidney hypophosphatemia and kidney tubular acidosis. We detected pathogenic variants in 26 different genes confirming a genetic diagnosis of tubulopathy in 29% of cases. In 16 cases (2.1%) the genetic testing changed the clinical diagnosis. The diagnosis of familial hypercalcemia with hypocalciuria was confirmed in 12% of cases. Thus, our work demonstrates the genetic origin of tubulopathies in one out of three adult patients, half of the rate observed in children. Hence, establishing a precise diagnosis is crucial for patients, in order to guide care, to survey and prevent chronic complications, and for genetic counselling. At the same time, this work enhances our understanding of complex phenotypes and enriches the database with the causal variants described.

Background Gitelman 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. Methods To 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. Results We 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. Conclusions Heterozygous 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.

International audience; 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.

International audience; Gain-of-function mutations in with no lysine (K) 1 (WNK1) and WNK4 genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited disorder characterized by arterial hypertension and hyperkalemia with metabolic acidosis. More recently, FHHt-causing mutations in the Kelch-like 3-Cullin 3 (KLHL3-CUL3) E3 ubiquitin ligase complex have shed light on the importance of WNK's cellular degradation on renal ion transport. Using full exome sequencing for a 4-generation family and then targeted sequencing in other suspected cases, we have identified new missense variants in the WNK1 gene clustering in the short conserved acidic motif known to interact with the KLHL3-CUL3 ubiquitin complex. Affected subjects had an early onset of a hyperkalemic hyperchloremic phenotype, but normal blood pressure values"Functional experiments in Xenopus laevis oocytes and HEK293T cells demonstrated that these mutations strongly decrease the ubiquitination of the kidney-specific isoform KS-WNK1 by the KLHL3-CUL3 complex rather than the long ubiquitous catalytically active L-WNK1 isoform. A corresponding CRISPR/Cas9 engineered mouse model recapitulated both the clinical and biological phenotypes. Renal investigations showed increased activation of the Ste20 proline alanine-rich kinase-Na+-Cl- cotransporter (SPAK-NCC) phosphorylation cascade, associated with impaired ROMK apical expression in the distal part of the renal tubule. Together, these new WNK1 genetic variants highlight the importance of the KS-WNK1 isoform abundance on potassium homeostasis.

Prenatal diagnosis of hyperechogenic kidneys is associated with a wide range of etiologies and prognoses. The recent advances in fetal ultrasound associated with the development of next-generation sequencing for molecular analysis have enlarged the spectrum of etiologies, making antenatal diagnosis a very challenging discipline. Of the various known causes of hyperechogenic fetal kidneys, calcium and phosphate metabolism disorders represent a rare cause. An accurate diagnosis is crucial for providing appropriate genetic counseling and medical follow-up after birth. We report on three cases of fetal hyperechogenic kidneys corresponding to postnatal diagnosis of nephrocalcinosis. In all cases, antenatal ultrasound showed hyperechogenic kidneys of normal to large size from 22 gestational weeks, with a normal amount of amniotic fluid. Postnatal ultrasound follow-up showed nephrocalcinosis associated with hypercalcemia, hypercalciuria, elevated 1,25(OH)2-vitamin D, and suppressed parathyroid hormone levels. Molecular genetic analysis by next-generation sequencing performed after birth in the three newborns revealed biallelic pathogenic variants in the SLC34A1 gene, encoding the sodium/phosphate cotransporter type 2 (Npt2a), confirming the diagnosis of infantile hypercalcemia. 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.

Background Hypomagnesaemia with secondary hypocal-caemia (HSH) is a rare autosomal recessive disorder caused by pathogenic variants in TRPM6, encoding the channel-kinase transient receptor potential melastatin type 6. Patients have very low serum magnesium (Mg2+) levels and suffer from muscle cramps and seizures. Despite genetic testing, a subgroup of HSH patients remains without a diagnosis. Methods In this study, two families with an HSH phenotype but negative for TRPM6 pathogenic variants were subjected to whole exome sequencing. Using a complementary combination of biochemical and functional analyses in overexpression systems and patient-derived fibroblasts, the effect of the TRPM7-identified variants on Mg2+ transport was examined. Results For the first time, variants in TRPM7 were identified in two families as a potential cause for hereditary HSH. Patients suffer from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcaemia. In the first family, a splice site variant caused the incorporation of intron 1 sequences into the TRPM7 messenger RNA and generated a premature stop codon. As a consequence, patient-derived fibroblasts exhibit decreased cell growth. In the second family, a heterozygous missense variant in the pore domain resulted in decreased TRPM7 channel activity. Conclusions We establish TRPM7 as a prime candidate gene for autosomal dominant hypomagnesaemia and secondary hypocalcaemia. Screening of unresolved patients with hypocalcaemia and secondary hypocalcaemia may further establish TRPM7 pathogenic variants as a novel Mendelian disorder.