scholarly journals Deciphering the mutation spectrum in south Indian children with congenital anomalies of the kidney and urinary tract

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Ambili Narikot ◽  
Varsha Chhotusing Pardeshi ◽  
A. M. Shubha ◽  
Arpana Iyengar ◽  
Anil Vasudevan
Keyword(s):  
Urinary Tract ◽  
Congenital Anomalies ◽  
Genetic Diagnostics ◽  
Genetic Profile ◽  
Fetal Life ◽  
Indian Children ◽  
Next Generation Sequencing Technology ◽  
Pathogenic Variants ◽  
South Indian ◽  
Dysplastic Kidney

Abstract Background Congenital anomalies of the kidney and urinary tract (CAKUT) cover a spectrum of structural malformations that result from aberrant morphogenesis of kidney and urinary tract. It is the most prevalent cause of kidney failure in children. Hence, it is important from a clinical perspective to unravel the molecular etiology of kidney and urinary tract malformations. Causal variants in genes that direct various stages of development of kidney and urinary tract in fetal life have been identified in 5–20% of CAKUT patients from Western countries. Recent advances in next generation sequencing technology and decreasing cost offer the opportunity to characterize the genetic profile of CAKUT in Indian population and facilitate integration of genetic diagnostics in care of children with CAKUT. Methods Customized targeted panel sequencing was performed to identify pathogenic variants in 31 genes known to cause human CAKUT in 69 south Indian children with CAKUT. The NGS data was filtered using standardized pipeline and the variants were classified using ACMG criteria. Genotype and phenotype correlations were performed. Results The cohort consisted of children mostly with posterior urethral valve (PUV) (39.1%), vesico-ureteric reflux (VUR) (33.3%) and multi-cystic dysplastic kidney (MCDK) (7.2%). No pathogenic or likely pathogenic variants were identified in the study. Most of our variants (n = 39, 60%) were variants of unknown significance with 25.6% (10/39) of them were identified as potentially damaging but were novel variants. Conclusions The present study did not identify any disease-causing monogenic variants in the cohort. The absence of genetic cause may be due to limitations of panel-based testing and also due to higher proportion of children with abnormalities in lower urinary tract than hypodysplasia of kidneys. Clinical, larger targeted panel or whole exome sequencing may be a better method to characterize the genetic profile of Indians patients with CAKUT.

scholarly journals Deciphering the Mutation Spectrum in South Indian Children With Congenital Anomalies of the Kidney and Urinary Tract

2021 ◽  
Author(s):  
Ambili Narikot ◽  
Varsha Chhotusing Pardeshi ◽  
Shubha AM ◽  
Arpana Iyengar ◽  
Anil Vasudevan
Keyword(s):  
Urinary Tract ◽  
Congenital Anomalies ◽  
Posterior Urethral Valve ◽  
Genetic Diagnostics ◽  
Genetic Profile ◽  
Fetal Life ◽  
Indian Children ◽  
South Indian ◽  
Dysplastic Kidney ◽  
Urethral Valve

Abstract Background: Congenital anomalies of the kidney and urinary tract (CAKUT) cover a spectrum of structural malformations that result from aberrant morphogenesis of kidney and urinary tract. It is the most prevalent cause of kidney failure in children. Hence, it is important from a clinical perspective to unravel the molecular etiology of kidney and urinary tract malformations. Causal variants in genes that direct various stages of development of kidney and urinary tract in fetal life have been identified in 5–20 % of CAKUT patients from Western countries. Recent advances in next generation sequencing technology and decreasing cost offer the opportunity to characterize the genetic burden of CAKUT in Indian population and facilitate integration of genetic diagnostics in care of children with CAKUT. Methods: Customized targeted panel sequencing was performed to identify mutations in 31 genes known to cause human CAKUT in 69 south Indian children with CAKUT. The NGS data was filtered using standardized pipeline and the variants were classified using ACMG criteria. Genotype and phenotype correlations were performed. Results: The cohort consisted of children mostly with posterior urethral valve (PUV) (39.1%), vesico-ureteric reflux (VUR) (33.3%) and multi-cystic dysplastic kidney (MCDK) (7.2%). Likely pathogenic variants were identified in two genes (TNXB and CHD1L) in 2 children (9 %) with CAKUT. One child diagnosed with posterior urethral valve (PUV) had mutation in two different genes [TNXB (p. Gln286fs), and CHD1L (p. Ser837fs)], while second child with left duplex system had a single gene mutation in TNXB gene (p. Gln286fs). Conclusions: The present study identified novel monogenic mutations in only a small proportion of patients with CAKUT using a targeted gene panel. The low prevalence of genetic cause may be due to higher proportion of children with abnormalities in lower urinary tract than hypodysplasia of kidneys. Clinical or whole exome sequencing may be a better method to characterize the genetic profile of Indians patients with CAKUT.

scholarly journals Unique association of multiple endocrine neoplasia 2A and congenital anomalies of the kidney and urinary tract in a child with a RET mutation

2019 ◽  
Vol 12 (8) ◽  
pp. e229904
Author(s):  
Olivia R Wood ◽  
Tobias Else ◽  
Matthew G Sampson
Keyword(s):  
Urinary Tract ◽  
Congenital Anomalies ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Multicystic Dysplastic Kidney ◽  
Pathogenic Variants ◽  
Endocrine Neoplasia ◽  
Dysplastic Kidney ◽  
Multiple Endocrine Neoplasia 2A ◽  
Unique Association

Pathogenic variants in the RET gene can cause isolated and multi-system diseases. We report a patient diagnosed prenatally with unilateral multicystic dysplastic kidney and genitourinary abnormality whose mother had multiple endocrine neoplasia type 2A (MEN2A). Targeted RET sequencing found the same pathogenic variant p.C618S in the child as her mother. The child is followed by paediatric nephrology for congenital anomalies of the kidney and urinary tract (CAKUT) and by endocrine oncology for surveillance for MEN2A-related endocrine tumours. While implicated in each of these conditions individually, RET variants have never been reported to cause MEN2A and CAKUT together. This child’s family history prompted RET sequencing, resulting in presymptomatic, personalised care for MEN2A. However, this case supports the idea that genetic screening of RET (and many other genes) in patients with CAKUT may lead to molecular diagnoses that potentially improve their health through precision care.

scholarly journals Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT)

2020 ◽  
Vol 22 (10) ◽  
pp. 1673-1681 ◽  
Author(s):  
Chen-Han Wilfred Wu ◽  
Nina Mann ◽  
Makiko Nakayama ◽  
Dervla M. Connaughton ◽  
Rufeng Dai ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Congenital Anomalies ◽  
Pathogenic Variants

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

2020 ◽  
Vol 9 (3) ◽  
pp. 751 ◽  
Author(s):  
Yo Han Ahn ◽  
Chung Lee ◽  
Nayoung K. D. Kim ◽  
Eujin Park ◽  
Hee Gyung Kang ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Congenital Anomalies ◽  
Genetic Diagnosis ◽  
Copy Number Variations ◽  
Single Nucleotide Variants ◽  
Korean Children ◽  
Targeted Exome Sequencing ◽  
Genetic Causes ◽  
Pathogenic Variants

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.

scholarly journals DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract

2019 ◽  
Author(s):  
Alexandria T.M. Blackburn ◽  
Nasim Bekheirnia ◽  
Vanessa C. Uma ◽  
Jill A. Rosenfeld ◽  
Matthew N. Bainbridge ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Congenital Anomalies ◽  
De Novo ◽  
Model Organism ◽  
Pathogenic Mutation ◽  
Clinical Syndrome ◽  
Loss Of Function ◽  
Large Database ◽  
Pathogenic Variants ◽  
Clinical Exome Sequencing

ABSTRACTPurposeHaploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A mutations.MethodsA large database of clinical exome sequencing (ES) was queried for de novo DYRK1A mutations and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development.ResultsPhenotypic details and mutations of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic mutation in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom present with CAKUT/GD. Studies in Xenopus embryos demonstrate that knockdown of Dyrk1a disrupts the development of segments of developing embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by co-injecting wildtype human DYRK1A RNA, but not with truncated DYRK1AR205* RNA.ConclusionEvidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss of function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

scholarly journals Evaluation of Insertion/deletion (I/D) Polymorphisms of ACE Gene in Congenital Anomalies of The Kidney and Urinary Tract From a Brazilian Pediatric Population

2021 ◽  
Author(s):  
Pedro Antunes Pousa ◽  
Tamires Sara Campos Mendonça ◽  
Larissa Marques Fonseca ◽  
Eduardo Araújo Oliveira ◽  
André Rolim Belisário ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Angiotensin Ii ◽  
Congenital Anomalies ◽  
Complex Disease ◽  
Pediatric Population ◽  
Allelic Frequency ◽  
Multicystic Dysplastic Kidney ◽  
Control Group ◽  
Healthy Controls ◽  
Dysplastic Kidney

Abstract Background: Congenital Anomalies of the Kidney and the Urinary Tract (CAKUT) are defined as a heterogeneous group of anomalies that resulted from defects in kidney and urinary tract embryogenesis. CAKUT have a complex etiology. Genetic, epigenetic and environmental factors have been investigated in this context. Angiotensin II is a potent vasoconstrictor and exerts an important role in kidney embryogenesis. The angiotensin-converting enzyme (ACE) converts Angiotensin I into Angiotensin II and ACE gene has insertion/deletion (I/D) polymorphisms that have been evaluated in several nephropathies. This study aimed to evaluate whether the I/D polymorphisms of ACE gene are associated with any CAKUT phenotype or CAKUT in general. Methods and Results: Our study was performed with 225 pediatric patients diagnosed with CAKUT and 210 age-and-sex matched healthy controls. ACE I/D alleles were analysed by real-time polymerase chain reaction (RT-PCR). The distribution of ACE I/D polymorphisms were compared between CAKUT patients and healthy controls, as well between ureteropelvic junction obstruction (UPJO), vesicoureteral reflux (VUR), multicystic dysplastic kidney (MCDK) phenotypes and control group. No statistical association of ACE I/D genotypes and allelic frequency between patients and controls was found among general CAKUT and UPJO, VUR and MCDK phenotypes. Conclusion: Although CAKUT is a complex disease and the ACE gene may exert a role in kidney embryogenesis, CAKUT was not associated with any ACE I/D polymorphisms in this Brazilian pediatric population.

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