Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT

Nicolaou, Nayia; Pulit, Sara L.; Nijman, Isaäc J.; Monroe, Glen R.; Feitz, W.F.J.; Schreuder, Michiel F.; Eerde, Albertien M. van; Jong, Tom P.V.M. de; Giltay, Jacques C.; Zwaag, Bert van der; Havenith, Marlies R.; Zwakenberg, Susan; Zanden, Loes F M van der; Poelmans, Geert; Cornelissen, Elisabeth A.M.; Lilien, Marc R.; Franke, Barbara; Roeleveld, Nel; Rooij, Iris A. L. M. van; Cuppen, Edwin; Bongers, Ernie M.H.F.; Giles, Rachel; Knoers, Nine V A M; Renkema, Kirsten Y.

doi:10.1038/ki.2015.319

Cited by 86 publications

(95 citation statements)

References 74 publications

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“…Our result was somewhat in accordance with that of Nicolaou's [32] study and indicated that the proportion of CAKUT/URA cases that followed a recessive model of inheritance was fairly low.…”

Section: Discussionsupporting

confidence: 92%

Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis

Wu¹,

Xu²,

Xie³

et al. 2017

Am J Nephrol

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Background: Few genetic studies have focused on unilateral renal agenesis (URA), which is a disorder with insidious clinical manifestations and a tendency to result in renal failure. We aimed to detect pathogenic mutations in nephrogenesis-related genes, which were identified by a literature review conducted among a large cohort of Chinese Han patients with URA. Methods: Totally, 86 unrelated URA patients were included. All URA patients were diagnosed by employing radiological methods. Patients with a solitary kidney owing to nephrectomy or renal atrophy due to secondary factors were excluded. Nine (10.5%) patients had a family history of abnormal nephrogenesis. Fifteen (17.4%) had other malformations in the urogenital system. All coding exons and adjacent intron regions of 25 genes were analyzed using next-generation sequencing and validated by Sanger sequencing and 100 ethnically matched healthy controls. Results: Ten conserved mutations (9 missense mutations and 1 deletion mutation) were identified in SALL1, EYA1, RET, HNF1B, DSTYK, WNT4, and SIX5. All mutations were novel or rare (frequency <0.1%) in the public databases and absent from the 100 healthy controls. Nine patients carried mutations in candidate genes. Most of the patients carried one single heterozygous mutation, except for 2, who respectively carried compound heterozygous mutations and 2 single heterozygous mutations. In addition, 2 patients shared the same mutation in DSTYK. Conclusion: A total of 10.5% of our URA cases could be explained by mutations in our candidate genes. The mutations in nephrogenesis-related genes in the Chinese Han patients with URA had a decentralized distribution without any hotspot mutations.

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Section: Discussionsupporting

confidence: 92%

Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis

Wu¹,

Xu²,

Xie³

et al. 2017

Am J Nephrol

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“…Similarly, Nicolaou et al [105] recently analyzed, through targeted NGS, 208 candidate genes (selected from studies on familial CAKUT, CAKUT-related multi-organ syndromes, and in vitro and in vivo models) in a phenotypically heterogeneous cohort of 453 CAKUT patients, which comprises the largest set of genes analyzed in a numerous cohort of CAKUT patients. They identified 148 candidate variants in 82 genes in 151 patients but only 5 disease-causing mutations (in HNF1β , PAX2 , SIX5 and UMOD genes) were defined as causal mutations.…”

Section: Genetic Resultsmentioning

confidence: 99%

Genetics of Congenital Anomalies of the Kidney and Urinary Tract: The Current State of Play

Capone

Morello

Taroni

et al. 2017

IJMS

106

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Congenital anomalies of the kidney and urinary tract (CAKUT) are the most frequent form of malformation at birth and represent the cause of 40–50% of pediatric and 7% of adult end-stage renal disease worldwide. The pathogenesis of CAKUT is based on the disturbance of normal nephrogenesis, secondary to environmental and genetic causes. Often CAKUT is the first clinical manifestation of a complex systemic disease, so an early molecular diagnosis can help the physician identify other subtle clinical manifestations, significantly affecting the management and prognosis of patients. The number of sporadic CAKUT cases explained by highly penetrant mutations in a single gene may have been overestimated over the years and a genetic diagnosis is missed in most cases, hence the importance of identifying new genetic approaches which can help unraveling the vast majority of unexplained CAKUT cases. The aim of our review is to clarify the current state of play and the future perspectives of the genetic bases of CAKUT.

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“…Previous studies on kidney anomalies using next-generation sequencing (NGS) have focused on specific disease entities like nephronophthisis or used broadly defined cohorts of patients with congenital anomalies of the kidney and urinary tract (CAKUT), also including cases with only minor anomalies. [5][6][7] It is estimated that variants in protein coding sequence or copy number variants (CNVs), which likely explain the phenotype, can currently be identified in 10%-16% of CAKUT patients. 8 In this study, we investigate the diagnostic yield of targeted-gene sequencing and whole-exome sequencing in a well-defined cohort of autopsied fetuses with severe prenatally diagnosed bilateral kidney anomalies in which previous genetic analyses have not uncovered an underlying cause; and we correlate our genetic findings with detailed phenotypic information, including post-mortem kidney histology.…”

Section: Introductionmentioning

confidence: 99%

Targeted gene sequencing and whole‐exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

et al. 2018

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Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel. We identified likely deleterious variants in 11 of 56 (20%) families. The kidney-gene analysis revealed likely deleterious variants in known kidney developmental genes in 6 fetuses and TMEM67 variants in 2 unrelated fetuses. Kidney histology was similar in the latter 2 fetuses-presenting a distinct prenatal form of nephronophthisis. Exome sequencing identified ROBO1 variants in one family and a GREB1L variant in another family. GREB1L and ROBO1 were added to our kidney-gene panel and additional variants were identified. Next-generation sequencing substantially contributes to identifying causes of fetal kidney anomalies. Genetic causes may be supported by histological examination of the kidneys. This is the first time that SLIT-ROBO signaling is implicated in human bilateral kidney agenesis.

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Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT

Cited by 86 publications

References 74 publications

Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis

Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal Agenesis

Genetics of Congenital Anomalies of the Kidney and Urinary Tract: The Current State of Play

Targeted gene sequencing and whole‐exome sequencing in autopsied fetuses with prenatally diagnosed kidney anomalies

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