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

Abstract

\n 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.