New insights from trio whole‐exome sequencing in the children with kidney disease: A single‐center retrospective cohort study

Abstract

Background Kidney disease of children markedly affects their health and development. Limited clinical data of early‐stage kidney disease render a tremendous challenge for the accurate diagnosis. Trio whole‐exome sequencing (Trio‐WES) is emerging as a first‐line diagnostic strategy in pediatric kidney disease, and shows important implications for the precision medicine strategies of children with kidney disease. Methods Trio‐WES was performed in 133 Chinese children with kidney disease and their parents. The results for casual variants in genes known to cause kidney disease were analyzed. We further assessed the genetic diagnostic yield and the clinical implications of genetic testing. Results An overall diagnostic yield of 52.63% (70/133) was found, and the diagnostic rates ranged from 44.74% to 59.62% in different clinical phenotypes. The diagnostic yield of the three groups of simple proteinuria, renal insufficiency, and “other” was 50%, 50%, and 54.55%, respectively. Eight‐seven diagnostic variants were identified in 70 probands with variants spanning 30 genes. The top 7 genes with diagnostic variants were COL4A5 (23, 26.44%), COL4A4 (13, 14.94%), ADCK4 (7, 8.05%), CLCN5 (3, 3.45%), ACE (3, 3.45%), PKD1 (3, 3.45%), and SLC12A3 (3, 3.45%), accounting for 63.22% of all variations in the cohort. Conclusions The retrospective cohort study summarized the clinical utility of genetic testing in 133 probands, and expanded the phenotypic and genetic profiles of kidney disease in children. Trio‐WES is an efficient diagnostic tool for children with kidney disease, which facilitates the clinical diagnosis and treatment. Our findings have important implications for the precise diagnosis of childhood nephropathy and may provide clinical guideline for disease management.

Genomic Approaches for Monogenic Kidney Diseases: A Comparative Review of Diagnostic Methods and Precision Medicine Implications

“…The corresponding diagnostic yield for non-specific CKD clinical presentations range from 32 to 52% for pediatric cases [45][46][47][48], 30 to 51% for pediatric/adult [49][50][51][52] and 9.3 to 34% for adult cases [53,54,63].…”

The Role of Genetic Testing in Pediatric Renal Diseases: Diagnostic, Prognostic, and Social Implications

“…Chen et al reported 44.74% for isolated hematuria, 59.62% for proteinuria and hematuria, 50% for simple proteinuria, 50% for renal insufficiency, and 54.55% for others. The mutated genes observed were ACE, ADCK4, COL4A4, COL4A5, CLCN5, PKD1, and SMARCAL1[9]. The diagnostic yield for the Bekheirnia et al study showed 42% for CAKUT, 79% for cystic kidney disease, 70% for proteinuria, and 67% for hematuria, and the observed mutated genes were COL4A4, HNF1B, PKD1, PKHD1, and WT1[10].…”

“…Huang et al reported 40.6% cases of nephrolithiasis, 40.6% of nephrocalcinosis, and 18.8% cases of nephrolithiasis+nephrocalcinosis with the highest total diagnostic yield of 78.1% among the included studies[8], followed by Chen et al, who reported a total diagnostic yield of 52%, while the spectrum of kidney diseases showed 28.87% cases of isolated hematuria, 39.1% of proteinuria and hematuria, 10.53% of simple proteinuria, 13.53% of renal insufficiency, and 8.27% of others[9]. Bekheirnia et al stated quite a closer total diagnostic yield of 51% with 26% cases of cystic kidney disease, 21% of congenital anomalies of the kidneys and urinary tracts (CAKUT), 20% of hematuria, and 11% of proteinuria[10].Rao et al reported 55.3% of cases of glomerular disease; CAKUT accounted for 15.9% of cases; 8.3% of cystic renal disease; 15.9% of renal tubular disease and renal calcinosis or nephrolithiasis; and 4.6% of CKD 3-5 stages, while the total diagnostic yield was 42.10%[11].…”

Development of an interpretable machine learning model associated with genetic indicators to identify Yin-deficiency constitution

“…Genetic indicators are objective microscopic information that is extremely valuable for precise, objective diagnosis of diseases [ 19 ]. Relevant studies have shown that there were differences in gene expression between YinDC and balanced constitution (BC) [ 20 ].…”