Results of targeted next-generation sequencing in children with cystic kidney diseases often change the clinical diagnosis

Abstract

Cystic kidney diseases are a very heterogeneous group of chronic kidney diseases. The diagnosis is usually based on clinical and ultrasound characteristics and the final diagnosis is often difficult to be made. Next-generation sequencing (NGS) may help the clinicians to find the correct final diagnosis. The aim of our study was to test the diagnostic yield of NGS and its ability to improve the diagnosis precision in a heterogeneous group of children with cystic kidney diseases. Next-generation sequencing of genes responsible for the formation of cystic kidneys was performed in 31 unrelated patients with various clinically diagnosed cystic kidney diseases gathered at the Department of Pediatrics of Motol University Hospital in Prague between 2013 and 2018. The underlying pathogenic variants were detected in 71% of patients (n = 22), no or only one (in case of autosomal recessive inheritance) pathogenic variant was found in 29% of patients (n = 9). The result of NGS correlated with the clinical diagnosis made before the NGS in 55% of patients (n = 17), in the remaining 14 children (45%) the result of NGS revealed another type of cystic kidney disease that was suspected clinically before or did not find causal mutation in suspected genes. The most common unexpected findings were variants in nephronophthisis (NPHP) genes in children with clinically suspected autosomal recessive polycystic kidney disease (ARPKD, n = 4). Overall, 24 pathogenic or probably pathogenic variants were detected in the PKHD1 gene, 8 variants in the TMEM67 gene, 4 variants in the PKD1 gene, 2 variants in the HNF1B gene and 2 variants in BBS1 and NPHP1 genes, respectively. NGS is a valuable tool in the diagnostics of various forms of cystic kidney diseases. Its results changed the clinically based diagnoses in 16% (n = 5) of the children.

Autosomal recessive polycystic kidney disease: case report of a newborn with rare PKHD1 mutation, rapid renal enlargement and early fatal outcome

“…These methods, providing precise genomic information, make the use of invasive investigations, like renal biopsy in ARPKD, no longer necessary, and allow to define more accurate prognoses. Indeed, when promptly obtained, they may guide and support clinicians and guarantee to the patients the most appropriate clinical management, avoiding futile and/or disproportionate treatments, as well as further unnecessary separations between children and their parents [27]. Then, in critical situations, as in our patient, the attention may shift from the invasive approach to a different goal, which is the reduction in suffering.…”

Autosomal recessive polycystic kidney disease: case report of a newborn with rare PKHD1 mutation, rapid renal enlargement and early fatal outcome

“…These methods, providing precise genomic information, make the use of invasive investigations, like renal biopsy in ARPKD, no longer necessary, and allow to de ne more accurate prognoses. Indeed, when promptly obtained, they may guide and support clinicians and guarantee to the patients the most appropriate clinical management, avoiding futile and/or disproportionate treatments, as well as further unnecessary separations between children and their parents [27]. Then, in critical situations, as in our patient, the attention may shift from the invasive approach to a different goal, which is the reduction in suffering.…”

Molecular Pathophysiology of Autosomal Recessive Polycystic Kidney Disease

“…As an alternative, methods such as next generation sequencing have become of interest as techniques that can simultaneously and efficiently analyze multiple candidate genes in a unique test, at relative low cost. In rare cases, mutations in two genes can even be observed in children with severe neonatal clinical phenotype [ 4 , 33 , 35 ].…”