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

Ahn, Yo Han; Lee, Chung; Kim, Nayoung K.D.; Park, Eujin; Kang, Hee Gyung; Ha, Il Soo; Park, Woong-Yang; Cheong, Hae Il

doi:10.3390/jcm9030751

Cited by 23 publications

(27 citation statements)

References 50 publications

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“…Pathogenic CNVs, recognizably important etiological factors underlying renal hypodysplasia (Sanna-Cherchi et al, 2012;Verbitsky et al, 2019), are recommended to be detected by arraybased technologies. However, consistent with prior reports on the use of targeted exome sequencing as a tool for identifying CNVs (Roberts et al, 2017;Ahn et al, 2020), our targeted exome sequencing and qPCR, we detected the deletion of the whole HNF1B and NPHP1 genes in 4 and 10 patients, respectively, but no additional CNVs were identified using array CGH.…”

Section: Discussionsupporting

confidence: 90%

Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5

Wang

Yao

et al. 2021

Front. Genet.

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Renal hypodysplasia and cystic kidney diseases, the common non-glomerular causes of pediatric chronic kidney disease (CKD), are usually diagnosed by their clinical and imaging characteristics. The high degree of phenotypic heterogeneity, in both conditions, makes the correct final diagnosis dependent on genetic testing. It is not clear, however, whether the frequencies of damaged alleles vary among different ethnicities in children with non-glomerular CKD, and this will influence the strategy used for genetic testing. In this study, 69 unrelated children (40 boys, 29 girls) of predominantly Han Chinese ethnicity with stage 2–5 non-glomerular CKD caused by suspected renal hypodysplasia or cystic kidney diseases were enrolled and assessed by molecular analysis using proband-only targeted exome sequencing and array-comparative genomic hybridization. Targeted exome sequencing discovered genetic etiologies in 33 patients (47.8%) covering 10 distinct genetic disorders. The clinical diagnoses in 13/48 patients (27.1%) with suspected renal hypodysplasia were confirmed, and two patients were reclassified carrying mutations in nephronophthisis (NPHP) genes. The clinical diagnoses in 16/20 patients (80%) with suspected cystic kidney diseases were confirmed, and one patient was reclassified as carrying a deletion in the hepatocyte nuclear factor-1-beta gene (HNF1B). The diagnosis of one patient with unknown non-glomerular disease was elucidated. No copy number variations were identified in the 20 patients with negative targeted exome sequencing results. NPHP genes were the most common disease-causing genes in the patients with disease onsets above 6 years of age (14/45, 31.1%). The children with stage 2 and 3 CKD at onset were found to carry causative mutations in paired box gene 2 (PAX2) and HNF1B gene (11/24, 45.8%), whereas those with stage 4 and 5 CKD mostly carried causative mutations in NPHP genes (19/45, 42.2%). The causative genes were not suspected by the kidney imaging patterns at disease onset. Thus, our data show that in Chinese children with non-glomerular renal dysfunction caused by renal hypodysplasia and cystic kidney diseases, the common causative genes vary with age and CKD stage at disease onset. These findings have the potential to improve management and genetic counseling of these diseases in clinical practice.

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Section: Discussionsupporting

confidence: 90%

Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5

Wang

Yao

et al. 2021

Front. Genet.

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“…Targeted exome sequencing was designed to capture 60 genes that have been reported to cause CAKUT in humans or murine models. The detailed procedures of targeted exome sequencing, whole exome sequencing, and bioinformatic analyses have been described previously [ 18 , 19 ]. MLPA analysis was performed to determine the presence of copy number variations using a commercial kit (SALSA ® MLPA ® P241-E1 Probemix; MRC-Holland, Amsterdam, The Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations

Lim

Kim

Han

et al. 2020

JCM

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HNF1B mutations, one of the most common causes of congenital anomalies of the kidney and urinary tract, manifest as various renal and extrarenal phenotypes. We analyzed the genotype-phenotype correlations in 14 pediatric patients with HNF1B mutations. Genetic studies revealed total gene deletion in six patients (43%). All patients had bilateral renal abnormalities, primarily multiple renal cysts. Twelve patients exhibited progressive renal functional deterioration, and six of them progressed to kidney failure. The annual reduction in estimated glomerular filtration rate was−2.1 mL/min/1.73 m2. Diabetes developed in five patients (36%), including one patient with new-onset diabetes after transplantation. Neurological deficits were noted in three patients (21%), one with total gene deletion and two with missense mutations. Pancreatic abnormalities were more frequent in patients with missense mutations than in patients with other types of mutations. Genotype showed no significant correlation with renal outcomes or other extrarenal manifestations. The HNF1B scores at the times of onset and genetic diagnosis were <8 in two patients and one patient, respectively. Diagnosis of HNF1B mutations is clinically difficult because of extreme phenotypic variability and incomplete penetrance. Furthermore, some phenotypes develop with age. Therefore, patient age should be taken into consideration to increase the diagnostic rate, because some phenotypes develop with age.

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“…The difference in the diagnostic yield in current study when compared to other studies could be attributed due to differences in cohort size, type of CAKUT that constituted the cohort and, in the genes included for screening. For example, high diagnostic yield was seen in cohort of severe CAKUT phenotypes, syndromic cases, patients from consanguineous families and familial cases (47,48). It is possible that the mutations in genes in targeted panel are rare in Indian population (less than 1% of observed cases with CAKUT) or larger cohorts screening is essential to con rm the observation.…”

Section: Discussionmentioning

confidence: 99%

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

Narikot

Pardeshi

et al. 2021

Preprint

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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.

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

Cited by 23 publications

References 50 publications

Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5

Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5

Genotype and Phenotype Analyses in Pediatric Patients with HNF1B Mutations

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

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