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Targeted Exome Sequencing Identifies PBX1 as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract.

ABSTRACT: Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified. However, despite high-throughput sequencing studies, the cause of the disease remains unknown in most patients, and several studies support more complex inheritance and the role of environmental factors and/or epigenetics in the pathophysiology of CAKUT. Here, we report the targeted exome sequencing of 330 genes, including genes known to be involved in CAKUT and candidate genes, in a cohort of 204 unrelated patients with CAKUT; 45% of the patients were severe fetal cases. We identified pathogenic mutations in 36 of 204 (17.6%) patients. These mutations included five de novo heterozygous loss of function mutations/deletions in the PBX homeobox 1 gene (PBX1), a gene known to have a crucial role in kidney development. In contrast, the frequency of SOX17 and DSTYK variants recently reported as pathogenic in CAKUT did not indicate causality. These findings suggest that PBX1 is involved in monogenic CAKUT in humans and call into question the role of some gene variants recently reported as pathogenic in CAKUT. Targeted exome sequencing also proved to be an efficient and cost-effective strategy to identify pathogenic mutations and deletions in known CAKUT genes.

SUBMITTER: Heidet L

PROVIDER: S-EPMC5619971 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Whole-exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract.

Project description:BackgroundCongenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidneys, may also represent monogenic causes of CAKUT.MethodsWe here performed whole-exome sequencing (WES) in 541 families with CAKUT and generated four lists of CAKUT candidate genes: (A) 36 FOX genes showing high expression during renal development, (B) 4 FOX genes known to cause CAKUT to validate list A, (C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families and (D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes.ResultsTo prioritize potential novel CAKUT candidates in the FOX gene family, we overlapped 36 FOX genes (list A) with lists C and D of WES-derived CAKUT candidates. Intersection with list C identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals.ConclusionsWe hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

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Targeted Exome Sequencing Provided Comprehensive Genetic Diagnosis of Congenital Anomalies of the Kidney and Urinary Tract.

Project description:Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children. The search for genetic causes of CAKUT has led to genetic diagnosis in approximately 5-20 % of CAKUT patients from Western countries. In this study, genetic causes of CAKUT in Korean children were sought using targeted exome sequencing (TES) of 60 genes reported to cause CAKUT in human or murine models. We identified genetic causes in 13.8% of the 94 recruited patients. Pathogenic single nucleotide variants of five known disease-causing genes, HNF1B, PAX2, EYA1, UPK3A, and FRAS1 were found in 7 cases. Pathogenic copy number variations of 6 patients were found in HNF1B, EYA1, and CHD1L. Genetic abnormality types did not significantly differ according to CAKUT phenotypes. Patients with pathogenic variants of targeted genes had syndromic features more frequently than those without (p < 0.001). This is the first genetic analysis study of Korean patients with CAKUT. Only one-seventh of patients were found to have pathogenic mutations in known CAKUT-related genes, indicating that there are more CAKUT-causing genes or environmental factors to discover.

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Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.

Project description:BackgroundCongenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT.MethodsWe applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.ResultsIn 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%).ConclusionsWe identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

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Novel Insights into the Pathogenesis of Monogenic Congenital Anomalies of the Kidney and Urinary Tract.

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Whole Exome Sequencing in a Population With Severe Congenital Anomalies of Kidney and Urinary Tract.

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Congenital Anomalies of the Kidney and Urinary Tract and Adulthood risk of Urinary Tract Cancer.

Project description:IntroductionCongenital anomalies of the kidney and urinary tract (CAKUT) are the most common kidney diseases in childhood. Alterations in genes governing nephrogenesis may cause CAKUT, and in some cases may contribute to development of urinary tract (UT) tumors later in life. We aimed to assess the association between CAKUT and UT cancer in adulthood.MethodsWe conducted a population-based historical cohort study encompassing 1,510,042 recruits to the Israeli army between 1967 and 1997. CAKUT exposure was determined by army medical coding of CAKUT in childhood. Incidence of UT cancer (kidney, ureter, or bladder) was available through record linkage with the Israeli Cancer Registry. Recruits were followed from the prerecruitment assessment until cancer diagnosis, death, or study termination, in 2012. Cox proportional hazards models were constructed to estimate the hazard ratios (HRs) for UT cancer in participants with vs. without CAKUT.ResultsDuring a mean follow-up of 30.4 years, 2959 participants (2573 men and 386 women) developed UT cancer. Men with CAKUT exhibited an increased risk of UT cancer compared with men without CAKUT, yielding an adjusted HR of 1.98 (95% confidence interval [CI] 1.03-3.82). Among women CAKUT was associated with a HR of 5.88 (95% CI 2.19-15.76). Notably, upon stratification according to age of cancer diagnosis, the association between CAKUT and UT cancer was statistically significant only before 45 years of age in women and only after 45 years of age in men.ConclusionCAKUT is associated with a significantly increased risk of UT cancer, although the incidence and absolute risk remained quite low.

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Project description:Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.

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Congenital Anomalies of the Kidney and Urinary Tract: A Clinical Review.

Project description:Purpose of review:This review highlights the most common congenital anomalies of the kidney and urinary tract (CAKUT) that are encountered in pediatric practices. CAKUT are the most common cause of prenatally diagnosed developmental malformations and encompass a spectrum of disorders impacting lower urinary tract development as well as kidney development and function. In pediatric and adolescent populations, developmental abnormalities are the leading cause of end-stage kidney disease. The goal of this review is to provide pediatric providers a framework for appropriate clinical management as well as highlight when referral to subspecialty care is needed. Recent findings:While the exact etiologies of CAKUT are not completely defined, new evidence demonstrates that genetic and molecular changes impact embryonic kidney and urinary tract development. As a result, phenotypes and clinical outcomes may be affected. Summary:Because pediatric providers provide front-line care to children and adolescents with developmental kidney and urinary tract anomalies, updated knowledge of CAKUT pathogenesis, embryology, clinical management, and patient outcomes is needed. This manuscript reviews CAKUT etiologies and essential diagnostic, prognostic, and management strategies.

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