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Bardet-Biedl Syndrome (BBS) is an autosomal recessive non-motile ciliopathy, caused by mutations in more than twenty genes. Their expression leads to the production of BBSome-building proteins or chaperon-like proteins supporting its structure. The prevalence of the disease is estimated at 1: 140,000 - 160,000 of life births. Its main clinical features are retinal dystrophy, polydactyly, obesity, cognitive impairment, hypogonadism, genitourinary malformations, and kidney disease. BBS is characterized by heterogeneous clinical manifestation and the variable onset of signs and symptoms. We present a case series of eight pediatric patients with BBS (6 boys and 2 girls) observed in one clinical center including two pairs of siblings. The patients' age varies between 2 to 13 years (average age of diagnosis: 22 months). At presentation kidney disorders were observed in seven patients, polydactyly in six patients' obesity, and psychomotor development delay in two patients. In two patients with kidney disorders, the genetic tests were ordered at the age of 1 and 6 months due to the presence of symptoms suggesting BBS and having an older sibling with the diagnosis of the syndrome. The mutations in the following genes were confirmed: BBS10, MKKS, BBS7/BBS10, BBS7, BBS9. All described patients developed symptoms related to the urinary system and kidney-function impairment. Other most common symptoms are polydactyly and obesity. In one patient the obesity class 3 was diagnosed with multiple metabolic disorders. In six patients the developmental delay was diagnosed. The retinopathy was observed only in one, the oldest patient. Despite having the same mutations (siblings) or having mutations in the same gene, the phenotypes of the patients are different. We aimed to addresses gaps in understanding BBS by comparing our data and existing literature through a narrative review. This research includes longitudinal data and explores genotype-phenotype correlations of children with BBS. BBS exhibits diverse clinical features and genetic mutations, making diagnosis challenging despite defined criteria. Same mutations can result in different phenotypes. Children with constellations of polydactyly and/or kidney disorders and/or early-onset obesity should be managed towards BBS. Early diagnosis is crucial for effective monitoring and intervention to manage the multisystemic dysfunctions associated with BBS.
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Síndrome de Bardet-Biedl , Humanos , Síndrome de Bardet-Biedl/genética , Síndrome de Bardet-Biedl/diagnóstico , Síndrome de Bardet-Biedl/terapia , Niño , Masculino , Femenino , Preescolar , Adolescente , MutaciónRESUMEN
Introduction: Congenital anomalies of the kidney and urinary tract (CAKUT) represent the most common cause of chronic kidney disease in children. Although only 20% of cases can be genetically explained, the majority remain without an identified underlying etiology. The neurodevelopmental disorder Chung-Jansen syndrome (CHUJANS) is caused by haploinsufficiency of Pleckstrin homology domain-interacting protein (PHIP) and was previously associated with genital malformations. Anecdotal coincidence of CHUJANS and CAKUT prompted us to investigate whether urorenal malformations are part of the phenotypic spectrum of CHUJANS. Methods: Analysis of existing CHUJANS and CAKUT cohorts, consulting matchmaking platforms, and systematic literature review to look for additional patients with both CHUJANS and CAKUT. Prenatal expression studies in murine and human renal tissues to investigate the role for PHIP in kidney development. Results: We identified 4 novel and 8 published cases, indicating variable expressivity with a urorenogenital trait frequency of 5% to 35%. The prenatal expression studies supported a role for PHIP in normal kidney and urinary tract development. Conclusion: Pathogenic PHIP gene variants should be considered as causative in patients with syndromal CAKUT. Conversely, patients with CHUJANS should be clinically evaluated for urorenogenital manifestations. Because neurodevelopmental disorders are often associated with kidney phenotypes, an interdisciplinary re-evaluation offers promise in identifying incompletely penetrant kidney associations and uncovering novel molecular mechanisms of disturbed nephrogenesis.
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Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of childhood chronic kidney disease. Congenital nephrotic syndrome of the Finnish type (CNF) (MIM# 256300) is caused by biallelic variants in the gene NPHS1, encoding nephrin, an integral component of the kidney filtration barrier. No causal treatments exist, and children inevitably require kidney replacement therapy. In preparation for gene replacement therapy (GRT) in CNF, we established a quantifiable and reproducible phenotypic assessment of the nephrin-deficient CNF mouse model: 129/Sv-Nphs1tm1Rkl/J. We assessed the phenotypic spectrum of homozygous mice (Nphs1tm1Rkl/Nphs1tm1Rkl) compared to heterozygous controls (Nphs1tm1Rkl/Nphs1WT) by the following parameters: 1. cohort survival, 2. podocyte foot process (FP) density per glomerular basement membrane (GBM) using transmission electron microscopy, 3. tubular microcysts in brightfield microscopy, and 4. urinary albumin/creatinine ratios. Nphs1tm1Rkl/Nphs1tm1Rkl mice exhibited: 1. perinatal lethality with median survival of 1 day, 2. FP effacement with median FP density of 1.00 FP/µm GBM (2.12 FP/µm in controls), 3. tubular dilation with 65 microcysts per section (6.5 in controls), and 4. increased albumin/creatinine ratio of 238 g/g (4.1 g/g in controls). We here established four quantifiable phenotyping features of a CNF mouse model to facilitate future GRT studies by enabling sensitive detection of phenotypic improvements.
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Modelos Animales de Enfermedad , Proteínas de la Membrana , Ratones Noqueados , Síndrome Nefrótico , Fenotipo , Podocitos , Animales , Síndrome Nefrótico/genética , Síndrome Nefrótico/patología , Proteínas de la Membrana/genética , Ratones , Podocitos/metabolismo , Podocitos/patología , Masculino , Femenino , Membrana Basal Glomerular/patologíaRESUMEN
BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease in children and young adults. The most severe form of steroid-resistant nephrotic syndrome is congenital nephrotic syndrome Finnish type (CNSF), caused by biallelic loss-of-function variants in NPHS1, encoding nephrin. Since each of the 68 monogenic causes of steroid-resistant nephrotic syndrome represents a rare cause of the disease, tailoring therapeutic interventions to multiple molecular targets remains challenging, suggesting gene replacement therapy (GRT) as a viable alternative. To set the ground for a gene replacement study in vivo, we established rigorous, quantifiable, and reproducible phenotypic assessment of a conditional Nphs1 knockout mouse model. METHODS: By breeding a floxed Nphs1fl/- mouse (Nphs1tm1Afrn/J) previously studied for pancreatic ß-cell survival with a podocin promoter-driven Cre recombinase mouse model (Tg(NPHS2-Cre)295Lbh/J), we generated mice with podocyte-specific nephrin deficiency (Nphs1fl/fl NPHS2-Cre +). RESULTS: We observed a median survival to postnatal day P5 in nephrin-deficient mice, whereas heterozygous control mice and wild type (WT) control group showed 90% and 100% survival, respectively (at P50 days). Light microscopy analysis showed a significantly higher number of renal-tubular microcysts per kidney section in nephrin-deficient mice compared to the control groups (P < 0.0022). Transmission electron microscopy demonstrated reduced foot process (FP) density in nephrin-deficient mice compared to controls (P < 0.0001). Additionally, proteinuria quantitation using urine albumin-to-creatinine ratio (UACR) was significantly higher in nephrin-deficient mice compared to controls. CONCLUSIONS: This study represents the first comprehensive description of the kidney phenotype in a nephrin-deficient mouse model, laying the foundation for future gene replacement therapy endeavors.
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BACKGROUND: Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients < 25 years of age. Through exome sequencing, identification of > 65 monogenic causes has revealed insights into disease mechanisms of nephrotic syndrome (NS). METHODS: To elucidate novel monogenic causes of NS, we combined homozygosity mapping with exome sequencing in a worldwide cohort of 1649 pediatric patients with NS. RESULTS: We identified homozygous missense variants in MYO1C in two unrelated children with NS (c.292C > T, p.R98W; c.2273 A > T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes. We then performed structural modeling for the identified variants in PyMol using aligned shared regions from two available partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the myosin motor domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants. CONCLUSION: We here identified recessive variants in MYO1C as a potential novel cause of NS in children.
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BACKGROUND: Genetic variants that cause rare disorders may remain elusive even after expansive testing, such as exome sequencing. The diagnostic yield of genome sequencing, particularly after a negative evaluation, remains poorly defined. METHODS: We sequenced and analyzed the genomes of families with diverse phenotypes who were suspected to have a rare monogenic disease and for whom genetic testing had not revealed a diagnosis, as well as the genomes of a replication cohort at an independent clinical center. RESULTS: We sequenced the genomes of 822 families (744 in the initial cohort and 78 in the replication cohort) and made a molecular diagnosis in 218 of 744 families (29.3%). Of the 218 families, 61 (28.0%) - 8.2% of families in the initial cohort - had variants that required genome sequencing for identification, including coding variants, intronic variants, small structural variants, copy-neutral inversions, complex rearrangements, and tandem repeat expansions. Most families in which a molecular diagnosis was made after previous nondiagnostic exome sequencing (63.5%) had variants that could be detected by reanalysis of the exome-sequence data (53.4%) or by additional analytic methods, such as copy-number variant calling, to exome-sequence data (10.8%). We obtained similar results in the replication cohort: in 33% of the families in which a molecular diagnosis was made, or 8% of the cohort, genome sequencing was required, which showed the applicability of these findings to both research and clinical environments. CONCLUSIONS: The diagnostic yield of genome sequencing in a large, diverse research cohort and in a small clinical cohort of persons who had previously undergone genetic testing was approximately 8% and included several types of pathogenic variation that had not previously been detected by means of exome sequencing or other techniques. (Funded by the National Human Genome Research Institute and others.).
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Variación Genética , Enfermedades Raras , Secuenciación Completa del Genoma , Femenino , Humanos , Masculino , Estudios de Cohortes , Exoma , Secuenciación del Exoma , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/etnología , Enfermedades Genéticas Congénitas/genética , Pruebas Genéticas , Genoma Humano , Fenotipo , Enfermedades Raras/diagnóstico , Enfermedades Raras/etnología , Enfermedades Raras/genética , Análisis de Secuencia de ADN , Niño , Adolescente , Adulto Joven , AdultoRESUMEN
All eukaryotes share a common ancestor from roughly 1.5 - 1.8 billion years ago, a single-celled, swimming microbe known as LECA, the Last Eukaryotic Common Ancestor. Nearly half of the genes in modern eukaryotes were present in LECA, and many current genetic diseases and traits stem from these ancient molecular systems. To better understand these systems, we compared genes across modern organisms and identified a core set of 10,092 shared protein-coding gene families likely present in LECA, a quarter of which are uncharacterized. We then integrated >26,000 mass spectrometry proteomics analyses from 31 species to infer how these proteins interact in higher-order complexes. The resulting interactome describes the biochemical organization of LECA, revealing both known and new assemblies. We analyzed these ancient protein interactions to find new human gene-disease relationships for bone density and congenital birth defects, demonstrating the value of ancestral protein interactions for guiding functional genetics today.
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Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.
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Variaciones en el Número de Copia de ADN , Secuenciación del Exoma , Exoma , Enfermedades Raras , Humanos , Variaciones en el Número de Copia de ADN/genética , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Exoma/genética , Masculino , Femenino , Estudios de Cohortes , Pruebas Genéticas/métodosRESUMEN
Background: Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients <25 years of age. Through whole exome sequencing, identification of >65 monogenic causes has rendered insights into disease mechanisms of nephrotic syndrome. Methods: To elucidate novel monogenic causes of NS, we combined homozygosity mapping with ES in a worldwide cohort of 1649 pediatric patients with NS. Results: We identified homozygous missense variants in MYO1C in two unrelated children with nephrotic syndrome (c.292C>T, p.R98W; c.2273 A>T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1Cto be predominantly expressed in podocytes. We then performed structural modeling in molecular viewer PyMol using the super function aligning shared regions within both partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the Myosin Motor Domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants. Conclusion: We here identified recessive variants in MYO1C as a potential novel cause of nephrotic syndrome in children.
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Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease before the age of 25 yr. Nephrin, encoded by NPHS1, localizes to the slit diaphragm of glomerular podocytes and is the predominant structural component of the glomerular filtration barrier. Biallelic variants in NPHS1 can cause congenital nephrotic syndrome of the Finnish type, for which, to date, no causative therapy is available. Recently, adeno-associated virus (AAV) vectors targeting the glomerular podocyte have been assessed as a means for gene replacement therapy. Here, we established quantitative and reproducible phenotyping of a published, conditional Nphs1 knockout mouse model (Nphs1tm1.1Pgarg/J and Nphs2-Cre+) in preparation for a gene replacement study using AAV vectors. Nphs1 knockout mice (Nphs1fl/fl Nphs2-Cre+) exhibited 1) a median survival rate of 18 days (range: from 9 to 43 days; males: 16.5 days and females: 20 days); 2) an average foot process (FP) density of 1.0 FP/µm compared with 2.0 FP/µm in controls and a mean filtration slit density of 2.64 µm/µm2 compared with 4.36 µm/µm2 in controls; 3) a high number of proximal tubular microcysts; 4) the development of proteinuria within the first week of life as evidenced by urine albumin-to-creatinine ratios; and 5) significantly reduced levels of serum albumin and elevated blood urea nitrogen and creatinine levels. For none of these phenotypes, significant differences between sexes in Nphs1 knockout mice were observed. We quantitatively characterized five different phenotypic features of congenital nephrotic syndrome in Nphs1fl/fl Nphs2-Cre+ mice. Our results will facilitate future gene replacement therapy projects by allowing for sensitive detection of even subtle molecular effects.NEW & NOTEWORTHY To evaluate potential, even subtle molecular, therapeutic effects of gene replacement therapy (GRT) in a mouse model, prior rigorous quantifiable and reproducible disease phenotyping is necessary. Here, we, therefore, describe such a phenotyping effort in nephrin (Nphs1) knockout mice to establish the basis for GRT for congenital nephrotic syndrome. We believe that our findings set an important basis for upcoming/ongoing gene therapy approaches in the field of nephrology, especially for monogenic nephrotic syndrome.
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Proteínas de la Membrana , Ratones Noqueados , Síndrome Nefrótico , Fenotipo , Podocitos , Animales , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Femenino , Masculino , Síndrome Nefrótico/genética , Síndrome Nefrótico/terapia , Podocitos/metabolismo , Modelos Animales de Enfermedad , Terapia Genética/métodos , Ratones , Vectores GenéticosRESUMEN
CELSR3 codes for a planar cell polarity protein. We describe twelve affected individuals from eleven independent families with bi-allelic variants in CELSR3. Affected individuals presented with an overlapping phenotypic spectrum comprising central nervous system (CNS) anomalies (7/12), combined CNS anomalies and congenital anomalies of the kidneys and urinary tract (CAKUT) (3/12) and CAKUT only (2/12). Computational simulation of the 3D protein structure suggests the position of the identified variants to be implicated in penetrance and phenotype expression. CELSR3 immunolocalization in human embryonic urinary tract and transient suppression and rescue experiments of Celsr3 in fluorescent zebrafish reporter lines further support an embryonic role of CELSR3 in CNS and urinary tract formation.
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BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is the second most common cause of kidney failure in children and adults under the age of 20 years. Previously, we were able to detect by exome sequencing (ES) a known monogenic cause of SRNS in 25-30% of affected families. However, ES falls short of detecting copy number variants (CNV). Therefore, we hypothesized that causal CNVs could be detected in a large SRNS cohort. METHODS: We performed genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on a cohort of 138 SRNS families, in whom we previously did not identify a genetic cause through ES. We evaluated ES and CNV data for variants in 60 known SRNS genes and in 13 genes in which variants are known to cause a phenocopy of SRNS. We applied previously published, predefined criteria for CNV evaluation. RESULTS: We detected a novel CNV in two genes in 2 out of 138 families (1.5%). The 9,673 bp homozygous deletion in PLCE1 and the 6,790 bp homozygous deletion in NPHS2 were confirmed across the breakpoints by PCR and Sanger sequencing. CONCLUSIONS: We confirmed that CNV analysis can identify the genetic cause in SRNS families that remained unsolved after ES. Though the rate of detected CNVs is minor, CNV analysis can be used when there are no other genetic causes identified. Causative CNVs are less common in SRNS than in other monogenic kidney diseases, such as congenital anomalies of the kidneys and urinary tract, where the detection rate was 5.3%. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Síndrome Nefrótico , Adulto , Niño , Humanos , Adulto Joven , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Predisposición Genética a la Enfermedad , Homocigoto , Mutación , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/genética , Síndrome Nefrótico/congénito , Eliminación de SecuenciaRESUMEN
Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium. Each family's CNV data was analyzed using the seqr platform and candidate CNVs classified using the 2020 ACMG/ClinGen CNV interpretation standards. We developed additional evidence criteria to address situations not covered by the current standards. The addition of CNV calling to exome analysis identified causal CNVs for 173 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb with estimates that 44% would not have been detected by standard chromosomal microarrays. The causal CNVs consisted of 141 deletions, 15 duplications, 4 suspected complex structural variants (SVs), 3 insertions and 10 complex SVs, the latter two groups being identified by orthogonal validation methods. We interpreted 153 CNVs as likely pathogenic/pathogenic and 20 CNVs as high interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.
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INTRODUCTION: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in the first 3 decades of life. Over 40 genes have been identified as causative for isolated human CAKUT. However, many genes remain unknown, and the prioritization of potential CAKUT candidate genes is challenging. To develop an independent approach to prioritize CAKUT candidate genes, we hypothesized that monogenic CAKUT genes are most likely co-expressed along a temporal axis during kidney development and that genes with coinciding high expression may represent strong novel CAKUT candidate genes. METHODS: We analyzed single-cell mRNA (sc-mRNA) transcriptomics data of human fetal kidney for temporal sc-mRNA co-expression of 40 known CAKUT genes. A maximum of high expression in consecutive timepoints of kidney development was found for four of the 40 genes (EYA1, SIX1, SIX2, and ITGA8) in nephron progenitor cells a, b, c, d (NPCa-d). We concluded that NPCa-d are relevant for CAKUT pathogenesis and intersected two lists of CAKUT candidate genes resulting from unbiased whole-exome sequencing (WES) with the 100 highest expressed genes in NPCa-d. RESULTS: Intersection of the 100 highest expressed genes in NPCa-d with WES-derived CAKUT candidate genes identified an overlap with the candidate genes KIF19, TRIM36, USP35, CHTF18, in each of which a biallelic variant was detected in different families with CAKUT. CONCLUSION: Sc-mRNA expression data of human fetal kidney can be utilized to prioritize WES-derived CAKUT candidate genes. KIF19, TRIM36, USP35, and CHTF18 may represent strong novel candidate genes for CAKUT.
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Transcriptoma , Sistema Urinario , Humanos , Riñón/anomalías , Sistema Urinario/anomalías , ARN Mensajero , Proteínas de Homeodominio , EndopeptidasasRESUMEN
Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a large variety of malformations that arise from defective kidney or urinary tract development and frequently lead to kidney failure. The clinical spectrum ranges from severe malformations, such as renal agenesis, to potentially milder manifestations, such as vesicoureteral reflux. Almost 50% of cases of chronic kidney disease that manifest within the first three decades of life are caused by CAKUT. Evidence suggests that a large number of CAKUT are genetic in origin. To date, mutations in ~54 genes have been identified as monogenic causes of CAKUT, contributing to 12-20% of the aetiology of the disease. Pathogenic copy number variants have also been shown to cause CAKUT and can be detected in 4-11% of patients. Furthermore, environmental and epigenetic factors can increase the risk of CAKUT. The discovery of novel CAKUT-causing genes is challenging owing to variable expressivity, incomplete penetrance and variable genotype-phenotype correlation. However, such a discovery could ultimately lead to improvements in the accurate molecular genetic diagnosis, assessment of prognosis and multidisciplinary clinical management of patients with CAKUT, potentially including personalized therapeutic approaches.
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Insuficiencia Renal Crónica , Sistema Urinario , Anomalías Urogenitales , Reflujo Vesicoureteral , Humanos , Riñón/anomalías , Anomalías Urogenitales/diagnóstico , Sistema Urinario/anomalías , Reflujo Vesicoureteral/genética , Insuficiencia Renal Crónica/genéticaRESUMEN
Neurogenic bladder is caused by disruption of neuronal pathways regulating bladder relaxation and contraction. In severe cases, neurogenic bladder can lead to vesicoureteral reflux, hydroureter, and chronic kidney disease. These complications overlap with manifestations of congenital anomalies of the kidney and urinary tract (CAKUT). To identify novel monogenic causes of neurogenic bladder, we applied exome sequencing (ES) to our cohort of families with CAKUT. By ES, we have identified a homozygous missense variant (p.Gln184Arg) in CHRM5 (cholinergic receptor, muscarinic, 5) in a patient with neurogenic bladder and secondary complications of CAKUT. CHRM5 codes for a seven transmembrane-spanning G-protein-coupled muscarinic acetylcholine receptor. CHRM5 is shown to be expressed in murine and human bladder walls and is reported to cause bladder overactivity in Chrm5 knockout mice. We investigated CHRM5 as a potential novel candidate gene for neurogenic bladder with secondary complications of CAKUT. CHRM5 is similar to the cholinergic bladder neuron receptor CHRNA3, which Mann et al. published as the first monogenic cause of neurogenic bladder. However, functional in vitro studies did not reveal evidence to strengthen the status as a candidate gene. Discovering additional families with CHRM5 variants could help to further assess the genes' candidate status.
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Vejiga Urinaria Neurogénica , Sistema Urinario , Anomalías Urogenitales , Reflujo Vesicoureteral , Humanos , Ratones , Animales , Vejiga Urinaria Neurogénica/genética , Anomalías Urogenitales/genética , Reflujo Vesicoureteral/genética , Riñón/anomalías , Ratones NoqueadosRESUMEN
Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
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Estudio de Asociación del Genoma Completo , Síndrome Nefrótico , Humanos , Niño , Síndrome Nefrótico/genética , Predisposición Genética a la Enfermedad , Haplotipos , Factores de Riesgo , Polimorfismo de Nucleótido SimpleRESUMEN
AIM: The earlier the onset of proteinuria, the higher the incidence of genetic forms. Therefore, we aimed to analyse the spectrum of monogenic proteinuria in Egyptian children presenting at age <2 years. METHODS: The results of 27-gene panel or whole-exome sequencing were correlated with phenotype and treatment outcomes in 54 patients from 45 families. RESULTS: Disease-causing variants were identified in 29/45 (64.4%) families. Mutations often occurred in three podocytopathy genes: NPHS1, NPHS2 and PLCE1 (19 families). Some showed extrarenal manifestations. Additionally, mutations were detected in 10 other genes, including novel variants of OSGEP, SGPL1 and SYNPO2. COL4A variants phenocopied isolated steroid-resistant nephrotic syndrome (2/29 families, 6.9%). NPHS2 M1L was the single most common genetic finding beyond the age of 3 months (4/18 families, 22.2%). Biopsy results did not correlate with genotypes (n = 30). On renin-angiotensin-aldosterone system antagonists alone, partial and complete remission occurred in 3/24 (12.5%) patients with monogenic proteinuria each, whereas 6.3% (1/16) achieved complete remission on immunosuppression. CONCLUSION: Genotyping is mandatory to avoid biopsies and immunosuppression when proteinuria presents at age <2 years. Even with such a presentation, COL4A genes should be included. NPHS2 M1L was prevalent in Egyptian children (4 months-2 years) with proteinuria, demonstrating precision diagnostic utility.