Diagnostic application of exome sequencing in Chinese children with suspected inherited kidney diseases

Abstract

Background: Inherited kidney diseases (IKDs) are a group of kidney diseases characterized by abnormal kidney structure or function caused by genetic factors, but they are not easily diagnosed in childhood due to either nonspecific symptoms and signs or clinically silent symptoms in the early stages until the progressive stages, even end-stages. Early diagnosis of IKDs is very urgent for timely treatment and improving outcomes of patients. So far, the etiological diagnosis has been accelerated with the advance of clinical genetic technology, particularly the advent of next-generation sequencing (NGS) that is not only a powerful tool for prompt and accurate diagnosis of IKDs but also gives therapy guidance to decrease the risk of unnecessary and harmful interventions.Methods: The patients presenting with urinalysis abnormalities or structural abnormalities from 149 Chinese families were enrolled in this study. The clinical features of the patients were collected, and the potentially causative gene variants were detected using exome sequencing. The clinical diagnostic utility of the genetic testing was assessed after more detailed clinical data were analyzed.Result: In total, 55 patients identified having causative variants by exome sequencing were genetically diagnosed, encompassing 16 (29.1%) autosomal dominant IKDs, 16 (29.1%) autosomal recessive IKDs, and 23 (41.8%) X-linked IKDs, with 25 unreported and 45 reported variants. The diagnostic yield was 36.9%. The utility of the exome sequencing was accessed, 12 patients (21.8%) were confirmed to have suspected IKDs, 26 patients (47.3%) discerned the specific sub-types of clinical category, and 17 patients (30.9%) with unknown etiology or lack of typical manifestations were reclassified.Conclusion: Our study supported that genetic testing plays a crucial role in the early diagnosis for children with IKDs, which affected follow-up treatment and prognostic assessment in clinical practice. Moreover, the variant spectrum associated with IKDs was expanded.

Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure

“…The observed genetic detection of 45% is a relative high yield compared with that previously reported for single-center or selected pediatric CKD cohorts. 1 , 15 , 16 However, this relatively high genetic diagnostic yield is comparable to other Israeli nationwide exome sequencing studies performed in children with neurodevelopmental disorders. 17 Moreover, we found high percentages of monogenic cases in children even when there was no positive family history, consanguinity, or syndromic features (26%, 29%, and 32% respectively).…”

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

“…In Rao et al the diagnostic yield was 29.1% for glomelular diseases, 61.4% for cystic renal disease 17% for CAKUT, 62.3% for renal tubular disease/renal calcinosis and 23.9% for CKD[11]. The mutated genes in Gao et al study were COL4A3, COL4A4, COL4A5, CLCN5, NPHS1, PKD1, PKHD1, SMARCAL1, OCRL and others[12]. In a study by Vaisitti et al, the yield was 20.6% for CAKUT, 74.4% for ciliopathies, 24.2% for glomerulopathies, 45.5% for nephrolithiasis, 45% for tubulopathies, and 7.1% for others[1].…”

“…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]. Gao et al described that 41.8% of cases accounted for X-linked inherited kidney disease, while for both autosomal dominant and autosomal recessive inherited kidney disease, there were 29.1% of cases each, and the total diagnostic yield was 36.3%[12].Vaisitti et al reported that glomerular diseases accounted for 32.5%, ciliopathies for 20.4%, CAKUT for 17.8%, nephrolithiasis for 11.5%, tubular disease for 10.5%, and 7.3% for other diseases, and the total diagnostic yield was 37.1%[1]. Braun et al demonstrated 86.01% cases of nephrolithiasis and 13.99% cases of nephrocalcinosis, while the total diagnostic yield was 16.8%[13].…”