Dataset Information

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

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.

SUBMITTER: Narikot A

PROVIDER: S-EPMC8722277 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionCongenital anomalies of the kidney and urinary tract (CAKUT) corresponds to a spectrum of defects. Several large-cohort studies have used high-throughput sequencing to investigate the genetic risk of CAKUT during antenatal, childhood, and adulthood period. However, our knowledge of newborns with CAKUT is limited.MethodsThis multicenter retrospective cohort study explored the genetic spectrum of CAKUT in a Chinese neonatal cohort. Clinical data and whole exome sequencing (WES) data of 330 newborns clinically diagnosed with CAKUT were collected. WES data were analyzed for putative deleterious single nucleotide variants (SNVs) and potential disease-associated copy number variants (CNVs).ResultsIn this study, pathogenic variants were identified in 61 newborns (18.5%, 61/330), including 35 patients (57.4%) with SNVs, 25 patients (41%) with CNVs, and 1 patient with both an SNV and a CNV. Genetic diagnosis rates were significantly higher in patients with extrarenal manifestations (P＜0.001), especially in those with cardiovascular malformations (P＜0.05). SNVs in genes related to syndromic disorders (CAKUT with extrarenal manifestations) were common, affecting 20 patients (57.1%, 20/35). KMT2D was the most common gene (5 patients) and 17q12 deletion was the most common CNV (4 patients). Patient 110 was detected with both a CNV (17q12 deletion) and an SNV (a homozygous variant of SLC25A13). Among the newborns with positive genetic results, 22 (36.1%, 22/61) patients may benefit from a molecular diagnosis and change in clinical management (including early multidisciplinary treatment, disease-specific follow-up, and familial genetic counseling).ConclusionThis study shows the heterogeneous genetic etiologies in a Chinese CAKUT neonatal cohort by using WES. Patients with CAKUT who have extrarenal manifestations are more likely to harbor genetic diagnoses. Kabuki syndrome and 17q12 deletion syndrome were the most common genetic findings. Approximately 36.1% of the patients may benefit from molecular diagnoses and a change in clinical management.