The role of genetic testing in the diagnostic workflow of pediatric patients with kidney diseases: the experience of a single institution

Abstract

Purpose Inherited kidney diseases are among the leading causes of kidney failure in children, resulting in increased mortality, high healthcare costs and need for organ transplantation. Next-generation sequencing technologies can help in the diagnosis of rare monogenic conditions, allowing for optimized medical management and therapeutic choices. Methods Clinical exome sequencing (CES) was performed on a cohort of 191 pediatric patients from a single institution, followed by Sanger sequencing to confirm identified variants and for family segregation studies. Results All patients had a clinical diagnosis of kidney disease: the main disease categories were glomerular diseases (32.5%), ciliopathies (20.4%), CAKUT (17.8%), nephrolithiasis (11.5%) and tubular disease (10.5%). 7.3% of patients presented with other conditions. A conclusive genetic test, based on CES and Sanger validation, was obtained in 37.1% of patients. The highest detection rate was obtained for ciliopathies (74.4%), followed by nephrolithiasis (45.5%), tubular diseases (45%), while most glomerular diseases and CAKUT remained undiagnosed. Conclusions Results indicate that genetic testing consistently used in the diagnostic workflow of children with chronic kidney disease can (i) confirm clinical diagnosis, (ii) provide early diagnosis in the case of inherited conditions, (iii) find the genetic cause of previously unrecognized diseases and (iv) tailor transplantation programs.

Single-Center Experience of Pediatric Cystic Kidney Disease and Literature Review

“…Complete molecular mechanisms encompassing the structure and function of protein are difficult to identify from a single panel of genetic testing. Therefore, structural and functional protein studies may provide better evidence when the genetic mutation is not identified in standard testing [89][90][91]. Genetic testing would help plan or anticipate the natural course of illness, as in the present study CEP 290 mutation would have guided the clinicians and families for early renal replacement therapy or enrolling in renal transplant lists.…”

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

“…Pediatric kidney diseases include a wide range of disease entities with varying clinical manifestations, courses of development, and treatment choices. Children with end-stage renal disease constitute a greater portion of the monogenic condition population, accounting for almost 30% of children with chronic kidney disease (CKD) [1]. Globally, pediatric CKD has a severe impact and is linked to high cardiovascular and allcause death rates, as well as significant morbidity.…”

“…Rapidly, genomics is being incorporated into the standard of care for children and their families with kidney disease, primarily as a diagnostic tool but also to guide therapy [7]. The use of next-generation sequencing techniques has greatly increased the diagnostic yield in patients with inherited kidney disorders, according to findings of numerous groundbreaking studies [1,3,4]. In the present review, we aim to collect all potential evidence from relevant studies that reported the role of genetic testing in pediatric renal disease diagnostic, prognostic, and social implications.…”

“…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]. Braun et al reported a diagnostic yield of 13% for nephrolithiasis and 40% for nephrocalcinosis with OCRL as a mutated gene[13].…”

“…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].…”