Clinical Significance of the Cystic Phenotype in Alport Syndrome.

RATIONALE & OBJECTIVE: Alport syndrome (AS) is the most common genetic glomerular disease caused by mutations that affect type IV collagen. However, the clinical characteristics and significance of AS with kidney cysts are not well defined. This study investigated the prevalence and clinical significance of cystic kidney phenotype in AS. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: One hundred-eight patients with AS and a comparison cohort of 79 patients with IgA nephropathy (IgAN). Clinical, genetic, and imaging data were collected from medical records. EXPOSURE: Cystic kidney phenotype evaluated by ultrasonography and defined as the presence of≥3 cysts in each kidney; demographic characteristics and estimated glomerular filtration rate (eGFR) at disease onset. OUTCOME: Cystic kidney phenotype in the AS and IgAN cohorts; time to chronic kidney disease (CKD) stage 3b and longitudinal changes in eGFR in the AS cohort. ANALYTICAL APPROACH: Logistic regression analysis to test independent strengths of associations of clinical/demographic features with the binary outcome of cystic phenotype. Survival analysis for the outcome of reaching CKD stage 3b and linear mixed models for changes in eGFR over time in the AS cohort. RESULTS: We studied 108 patients with AS; 76 (70%) had a genetic diagnosis. Autosomal dominant AS was prevalent, accounting for 68% of patients with a genetic diagnosis. Cystic kidney phenotype was observed in 38% of patients with AS and was associated with normal-sized kidneys in all but 3 patients, who showed increased total kidney volume, mimicking autosomal dominant polycystic kidney disease. The prevalence of cystic kidney phenotype was significantly higher in patients with AS when compared with the group of patients with IgAN (42% vs 19%; P=0.002). Patients with the cystic kidney phenotype were older and had more marked reduction in eGFR than patients without cystic changes. Among patients with AS, the cystic phenotype was associated with older age and a faster decline eGFR. LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: Cystic kidney phenotype is a common finding in AS. The cystic kidney phenotype is a common finding in AS, suggesting a possible role in cystogenesis for the genetic variants that cause this disease. PLAIN-LANGUAGE SUMMARY: Hematuria is the classic renal presentation of Alport syndrome (AS), a hereditary glomerulopathy caused by pathogenic variants of the COL4A3-5 genes. An atypical kidney cystic phenotype has been rarely reported in individuals with these variants. To determine the prevalence of kidney cysts, we performed abdominal ultrasonography in a large group of patients with AS and a comparison group of patients with another glomerular kidney disease, IgA nephropathy (IgAN). Multiple kidney cysts, usually with normal kidney volume, were found in 38% of patients with AS. A few patients' kidney volumes were large enough to mimic a different hereditary cystic kidney disease, autosomal dominant polycystic kidney disease. The overall prevalence of kidney cysts in AS was more than double that observed in the well-matched comparison group with IgAN. These findings emphasize the high prevalence of cystic kidney phenotype in AS, suggesting a likely association between the genetic variants that cause this disease and the development of kidney cysts.

Prenatal vs postnatal diagnosis of 22q11.2 deletion syndrome: cardiac and noncardiac outcomes through 1 year of age.

BACKGROUND: The 22q11.2 deletion syndrome is the most common microdeletion syndrome and is frequently associated with congenital heart disease. Prenatal diagnosis of 22q11.2 deletion syndrome is increasingly offered. It is unknown whether there is a clinical benefit to prenatal detection as compared with postnatal diagnosis. OBJECTIVE: This study aimed to determine differences in perinatal and infant outcomes between patients with prenatal and postnatal diagnosis of 22q11.2 deletion syndrome. STUDY DESIGN: This was a retrospective cohort study across multiple international centers (30 sites, 4 continents) from 2006 to 2019. Participants were fetuses, neonates, or infants with a genetic diagnosis of 22q11.2 deletion syndrome by 1 year of age with or without congenital heart disease; those with prenatal diagnosis or suspicion (suggestive ultrasound findings and/or high-risk cell-free fetal DNA screen for 22q11.2 deletion syndrome with postnatal confirmation) were compared with those with postnatal diagnosis. Perinatal management, cardiac and noncardiac morbidity, and mortality by 1 year were assessed. Outcomes were adjusted for presence of critical congenital heart disease, gestational age at birth, and site. RESULTS: A total of 625 fetuses, neonates, or infants with 22q11.2 deletion syndrome (53.4% male) were included: 259 fetuses were prenatally diagnosed (156 [60.2%] were live-born) and 122 neonates were prenatally suspected with postnatal confirmation, whereas 244 infants were postnatally diagnosed. In the live-born cohort (n=522), 1-year mortality was 5.9%, which did not differ between groups but differed by the presence of critical congenital heart disease (hazard ratio, 4.18; 95% confidence interval, 1.56-11.18; P<.001) and gestational age at birth (hazard ratio, 0.78 per week; 95% confidence interval, 0.69-0.89; P<.001). Adjusting for critical congenital heart disease and gestational age at birth, the prenatal cohort was less likely to deliver at a local community hospital (5.1% vs 38.2%; odds ratio, 0.11; 95% confidence interval, 0.06-0.23; P<.001), experience neonatal cardiac decompensation (1.3% vs 5.0%; odds ratio, 0.11; 95% confidence interval, 0.03-0.49; P=.004), or have failure to thrive by 1 year (43.4% vs 50.3%; odds ratio, 0.58; 95% confidence interval, 0.36-0.91; P=.019). CONCLUSION: Prenatal detection of 22q11.2 deletion syndrome was associated with improved delivery management and less cardiac and noncardiac morbidity, but not mortality, compared with postnatal detection.

Rare Single Nucleotide and Copy Number Variants and the Etiology of Congenital Obstructive Uropathy: Implications for Genetic Diagnosis.

SIGNIFICANCE STATEMENT: Congenital obstructive uropathy (COU) is a prevalent human developmental defect with highly heterogeneous clinical presentations and outcomes. Genetics may refine diagnosis, prognosis, and treatment, but the genomic architecture of COU is largely unknown. Comprehensive genomic screening study of 733 cases with three distinct COU subphenotypes revealed disease etiology in 10.0% of them. We detected no significant differences in the overall diagnostic yield among COU subphenotypes, with characteristic variable expressivity of several mutant genes. Our findings therefore may legitimize a genetic first diagnostic approach for COU, especially when burdening clinical and imaging characterization is not complete or available. BACKGROUND: Congenital obstructive uropathy (COU) is a common cause of developmental defects of the urinary tract, with heterogeneous clinical presentation and outcome. Genetic analysis has the potential to elucidate the underlying diagnosis and help risk stratification. METHODS: We performed a comprehensive genomic screen of 733 independent COU cases, which consisted of individuals with ureteropelvic junction obstruction ( n =321), ureterovesical junction obstruction/congenital megaureter ( n =178), and COU not otherwise specified (COU-NOS; n =234). RESULTS: We identified pathogenic single nucleotide variants (SNVs) in 53 (7.2%) cases and genomic disorders (GDs) in 23 (3.1%) cases. We detected no significant differences in the overall diagnostic yield between COU sub-phenotypes, and pathogenic SNVs in several genes were associated to any of the three categories. Hence, although COU may appear phenotypically heterogeneous, COU phenotypes are likely to share common molecular bases. On the other hand, mutations in TNXB were more often identified in COU-NOS cases, demonstrating the diagnostic challenge in discriminating COU from hydronephrosis secondary to vesicoureteral reflux, particularly when diagnostic imaging is incomplete. Pathogenic SNVs in only six genes were found in more than one individual, supporting high genetic heterogeneity. Finally, convergence between data on SNVs and GDs suggest MYH11 as a dosage-sensitive gene possibly correlating with severity of COU. CONCLUSIONS: We established a genomic diagnosis in 10.0% of COU individuals. The findings underscore the urgent need to identify novel genetic susceptibility factors to COU to better define the natural history of the remaining 90% of cases without a molecular diagnosis.

Identification of bi-allelic LFNG variants in three patients and further clinical and molecular refinement of spondylocostal dysostosis 3.

Spondylocostal dysostosis (SCD), a condition characterized by multiple segmentation defects of the vertebrae and rib malformations, is caused by bi-allelic variants in one of the genes involved in the Notch signaling pathway that tunes the "segmentation clock" of somitogenesis: DLL3, HES7, LFNG, MESP2, RIPPLY2, and TBX6. To date, seven individuals with LFNG variants have been reported in the literature. In this study we describe two newborns and one fetus with SCD, who were found by trio-based exome sequencing (trio-ES) to carry homozygous (c.822-5C>T) or compound heterozygous (c.[863dup];[1063G>A]) and (c.[521G>T];[890T>G]) variants in LFNG. Notably, the c.822-5C>T change, affecting the polypyrimidine tract of intron 5, is the first non-coding variant reported in LFNG. This study further refines the clinical and molecular features of spondylocostal dysostosis 3 and adds to the numerous investigations supporting the usefulness of trio-ES approach in prenatal and neonatal settings.

Copy Number Variant Analysis and Genome-wide Association Study Identify Loci with Large Effect for Vesicoureteral Reflux.

BACKGROUND: Vesicoureteral reflux (VUR) is a common, familial genitourinary disorder, and a major cause of pediatric urinary tract infection (UTI) and kidney failure. The genetic basis of VUR is not well understood. METHODS: A diagnostic analysis sought rare, pathogenic copy number variant (CNV) disorders among 1737 patients with VUR. A GWAS was performed in 1395 patients and 5366 controls, of European ancestry. RESULTS: Altogether, 3% of VUR patients harbored an undiagnosed rare CNV disorder, such as the 1q21.1, 16p11.2, 22q11.21, and triple X syndromes ((OR, 3.12; 95% CI, 2.10 to 4.54; P=6.35×10-8) The GWAS identified three study-wide significant and five suggestive loci with large effects (ORs, 1.41-6.9), containing canonical developmental genes expressed in the developing urinary tract (WDPCP, OTX1, BMP5, VANGL1, and WNT5A). In particular, 3.3% of VUR patients were homozygous for an intronic variant in WDPCP (rs13013890; OR, 3.65; 95% CI, 2.39 to 5.56; P=1.86×10-9). This locus was associated with multiple genitourinary phenotypes in the UK Biobank and eMERGE studies. Analysis of Wnt5a mutant mice confirmed the role of Wnt5a signaling in bladder and ureteric morphogenesis. CONCLUSIONS: These data demonstrate the genetic heterogeneity of VUR. Altogether, 6% of patients with VUR harbored a rare CNV or a common variant genotype conferring an OR >3. Identification of these genetic risk factors has multiple implications for clinical care and for analysis of outcomes in VUR.

An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.

Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0 × 10-5 for novel LOF, increased to p = 4.1 × 10-6 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3 × 10-7). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10-14). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

Outcomes in pregnancies with a confined placental mosaicism and implications for prenatal screening using cell-free DNA.

PURPOSE: To assess the association between confined placental mosaicism (CPM) and adverse pregnancy outcome. METHODS: A retrospective cohort study was carried out evaluating the outcome of pregnancies with and without CPM involving a rare autosomal trisomy (RAT) or tetraploidy. Birthweight, gestational age at delivery, fetal growth restriction (FGR), Apgar score, neonatal intensive care admission, preterm delivery, and hypertensive disorders of pregnancy were considered. RESULTS: Overall 181 pregnancies with CPM and 757 controls were recruited. Outcome information was available for 69% of cases (n = 124) and 62% of controls (n = 468). CPM involving trisomy 16 (T16) was associated with increased incidence of birthweight <3rd centile (P = 0.007, odds ratio [OR] = 11.2, 95% confidence interval [CI] = 2.7-47.1) and preterm delivery (P = 0.029, OR = 10.2, 95% CI = 1.9-54.7). For the other RATs, an association with prenatally diagnosed FGR was not supported by birthweight data and there were no other strong associations with adverse outcomes. CONCLUSION: Excluding T16, the incidence of adverse pregnancy outcomes for pregnancies carrying a CPM is low. RATs can also be identified through genome-wide cell-free DNA screening. Because most of these will be attributable to CPMs, we conclude that this screening is of minimal benefit.

Discrepant molecular and clinical diagnoses in Beckwith-Wiedemann and Silver-Russell syndromes.

Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS) are two imprinting disorders associated with opposite molecular alterations in the 11p15.5 imprinting centres. Their clinical diagnosis is confirmed by molecular testing in 50-70% of patients. The authors from different reference centres for BWS and SRS have identified single patients with unexpected and even contradictory molecular findings in respect to the clinical diagnosis. These patients clinically do not fit the characteristic phenotypes of SRS or BWS, but illustrate their clinical heterogeneity. Thus, comprehensive molecular testing is essential for accurate diagnosis and appropriate management, to avoid premature clinical diagnosis and anxiety for the families.

Expanding the phenotype of MED 17 mutations: Description of two new cases and review of the literature.

We report the case of two siblings presenting with failure to thrive in early years, progressive microcephaly, moderate intellectual disability, developmental delay, ataxic gait and seizures with an identical EEG pattern, and minimal cerebellar atrophy. We ruled out the syndromic and metabolic causes of microcephaly and subsequently conducted a panel of genetic diagnostic tests, including the clinical exome sequencing which revealed compound heterozygous mutations in MED 17 gene in both patients. p.Glu16fs was found to be inherited from the mother and p.Gly253Arg from the father. This case along with review of the literature suggests that mutations in MED17 may define a phenotype characterized by progressive microcephaly, intellectual disability, seizures, cerebellar atrophy of variable degree, and ataxia. More cases are needed to define the phenotype-genotype correlation in MED17 mutations. However, basing on our findings, we recommend testing MED17 mutations in any patient presenting with two or more of the aforementioned signs and symptoms.

Comparative X-ray morphometry of prenatal osteogenesis imperfecta type 2 and thanatophoric dysplasia: a contribution to prenatal differential diagnosis.

OBJECTIVE: The purpose of the paper was to assess the morphometric parameters to improve the specificity of the ultrasound (US) signs for the early differential diagnosis between two lethal dysplasias, as thanatophoric dysplasia (TD) and osteogenesis imperfecta type 2 (OI-2). METHOD: The diaphyseal length and the bowed shape of long bones associated with vertebral body dimension assessment were investigated in a group of 14 pregnancy terminations carried out in the time period 2007-2013. The definitive diagnosis was established after pregnancy termination by means of skeletal standardized X-rays, histopathology and gene analysis. RESULTS: TD and OI-2 long bones were significantly shorter than controls. No significant differences were observed between the two dysplasias. The bowing angle was higher in OI-2; a true angulation or eventually axial displacement was present only in the latter. Furthermore, they did not show any evidence of vertebral collapse. The thanatophoric dysplasia presented less bowed long bones, and never true angulation. The spine was steadily characterized by flattened anterior vertebral bodies. CONCLUSION: Long bone shortening is not a sufficient and accurate sign for early sonographic differential diagnosis between TD and OI-2. Angled diaphysis, axial diaphyseal displacement and a conserved vertebral body height in the prenatal period support the diagnosis of osteogenesis imperfecta type 2, while moderately regular bowed diaphysis associated with platyspondyly that of thanatophoric dysplasia.

Mutations in DSTYK and dominant urinary tract malformations.

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood. METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies. RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases. CONCLUSIONS: We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

Tubulointerstitial nephritis is a dominant feature of hereditary apolipoprotein A-I amyloidosis.

Apolipoprotein A-I is the main protein of high-density lipoprotein particles, and is encoded by the APOA1 gene. Several APOA1 mutations have been found, either affecting the lecithin:cholesterol acyltransferase activity, determining familial HDL deficiency, or resulting in amyloid formation with prevalent deposits in the kidney and liver. Evaluation of familial tubulointerstitial nephritis in patients with the Leu75Pro APOA-I amyloidosis mutation resulted in the identification of 253 carriers belonging to 50 families from Brescia, Italy. A total of 219 mutation carriers underwent clinical, laboratory, and instrumental tests. Of these, 62% had renal, hepatic, and testicular disease; 38% were asymptomatic. The disease showed an age-dependent penetrance. Tubulointerstitial nephritis was diagnosed in 49% of the carriers, 13% of whom progressed to kidney failure requiring dialysis. Hepatic involvement with elevation of cholestasis indices was diagnosed in 30% of the carriers, 38% of whom developed portal hypertension. Impaired spermatogenesis and hypogonadism was found in 68% of male carriers. The cholesterol levels were lower than normal in 80% of the mutation carriers. Thus, tubulointerstitial nephritis was highly prevalent in this large series of patients with Leu75Pro apoA-I amyloidosis. Persistent elevation of alkaline phosphatase, reduced HDL cholesterol plasma levels, and hypogonadism in men are key diagnostic features of this form of amyloidosis.

Copy-number disorders are a common cause of congenital kidney malformations.

We examined the burden of large, rare, copy-number variants (CNVs) in 192 individuals with renal hypodysplasia (RHD) and replicated findings in 330 RHD cases from two independent cohorts. CNV distribution was significantly skewed toward larger gene-disrupting events in RHD cases compared to 4,733 ethnicity-matched controls (p = 4.8 × 10(-11)). This excess was attributable to known and novel (i.e., not present in any database or in the literature) genomic disorders. All together, 55/522 (10.5%) RHD cases harbored 34 distinct known genomic disorders, which were detected in only 0.2% of 13,839 population controls (p = 1.2 × 10(-58)). Another 32 (6.1%) RHD cases harbored large gene-disrupting CNVs that were absent from or extremely rare in the 13,839 population controls, identifying 38 potential novel or rare genomic disorders for this trait. Deletions at the HNF1B locus and the DiGeorge/velocardiofacial locus were most frequent. However, the majority of disorders were detected in a single individual. Genomic disorders were detected in 22.5% of individuals with multiple malformations and 14.5% of individuals with isolated urinary-tract defects; 14 individuals harbored two or more diagnostic or rare CNVs. Strikingly, the majority of the known CNV disorders detected in the RHD cohort have previous associations with developmental delay or neuropsychiatric diseases. Up to 16.6% of individuals with kidney malformations had a molecular diagnosis attributable to a copy-number disorder, suggesting kidney malformations as a sentinel manifestation of pathogenic genomic imbalances. A search for pathogenic CNVs should be considered in this population for the diagnosis of their specific genomic disorders and for the evaluation of the potential for developmental delay.

Uromodulin: from monogenic to multifactorial diseases.

Uromodulin, the major protein secreted in normal urine, is exclusively produced in the thick ascending limb (TAL) cells of the kidney. The exact role uromodulin (UMOD) plays in renal physiology remains enigmatic. UMOD has been linked to water/electrolyte balance and to kidney innate immunity and it is believed to protect against urinary tract infections and renal stones. A renewed interest in UMOD has been triggered by the identification of UMOD mutations as cause of hereditary dominant renal diseases, now referred to as uromodulin-associated kidney diseases (UAKDs), presenting with tubulointerstitial fibrosis, defective urinary concentration, hyperuricaemia and gout, and progressive renal failure. In UAKDs, the key primary pathogenetic event is a delayed intracellular trafficking of mutant UMOD, causing its intracellular accumulation. In the last decade, multiple genome-wide association studies have identified common variants in the UMOD gene, causing independent susceptibility to chronic kidney disease (CKD) and hypertension, two complex traits representing major global health problems. The biological mechanism underlying the association between UMOD risk variants and susceptibility to CKD and hypertension was not understood until last year, when the link between UMOD and hypertension was found to be caused by overactivation of the TAL sodium-potassium-chloride co-transporter NKCC2, pointing to UMOD as a therapeutic target for lowering blood pressure and preserving renal function.

Interpreting mosaicism in chorionic villi: results of a monocentric series of 1001 mosaics in chorionic villi with follow-up amniocentesis.

OBJECTIVES: Chromosomal mosaicism in chorionic villi (CV) is detected in ~1-2% of cases. When a mosaic in CV is detected during prenatal diagnosis, a confirmatory karyotype should be performed on amniocytes to discriminate between a mosaic confined to the placenta [confined placental mosaicism (CPM)] and one generalized to the fetus [true fetal mosaicism (TFM)]. We determined the likelihood that any mosaic abnormalities identified through CV samples are confirmed in the fetus. METHODS: Over a period of 14 years, the laboratory analyzed both the cytotrophoblast and the mesenchyme of 60 347 CV samples. Cytogenetic results from CV samples showing mosaicism with follow-up amniocentesis were considered. The incidence of CPM and TFM and the risk of confirmation in the amniotic fluid (AF) were calculated. Uniparental disomy (UPD) was tested on ~300 cases at risk due to involvement of an imprinted chromosome. RESULTS: Overall, 1317 mosaic CV cases (2.18%) were detected, of which 1001 were subsequently investigated by amniocentesis. The overall risk of TFM was 13% and UPD incidence was 2.1%. CONCLUSIONS: The very large presented sample set and consistency in cytogenetic methodology, especially the analysis of both placental layers performed on all CV samples will enable genetic counselors to determine the risk of fetal involvement and the clinical relevance of an identified mosaic condition.

Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.

IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10⁻³²-3×10⁻¹°), with heterogeneity detected only at the PSMB9/TAP1 locus (I²â€Š= 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10⁻4). A seven-SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10⁻¹²8). This model paralleled the known East-West gradient in disease risk. Moreover, the prediction of a South-North axis was confirmed by registry data showing that the prevalence of IgAN-attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN.