Reverse phenotyping facilitates disease allele calling in exome sequencing of patients with CAKUT

Abstract

Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the leading cause of chronic kidney disease in children. In total, 174 monogenic causes of isolated or syndromic CAKUT are known. However, syndromic features may be overlooked when the initial clinical diagnosis of CAKUT is made. We hypothesized that the yield of a molecular genetic diagnosis by exome sequencing (ES) can be increased by applying reverse phenotyping, by re-examining the case for signs/symptoms of the suspected clinical syndrome that results from the genetic variant detected by ES. Methods: We conducted ES in an international cohort of 731 unrelated families with CAKUT. We evaluated ES data for variants in 174 genes, in which variants are known to cause isolated or syndromic CAKUT. In cases in which ES suggested a previously unreported syndromic phenotype, we conducted reverse phenotyping. Results: In 83 of 731 (11.4%) families, we detected a likely CAKUT-causing genetic variant consistent with an isolated or syndromic CAKUT phenotype. In 19 of these 83 families (22.9%), reverse phenotyping yielded syndromic clinical findings, thereby strengthening the genotype-phenotype correlation. Conclusion:We conclude that employing reverse phenotyping in the evaluation of syndromic CAKUT genes by ES provides an important tool to facilitate molecular genetic diagnostics in CAKUT.

Disease mechanisms of monogenic congenital anomalies of the kidney and urinary tract

“…Current data indicates that when a patient presents with CAKUT, genetic testing will reveal a monogenic cause of disease in 10%-20% of individuals (Mann, Braun, et al, 2019;Rasmussen et al, 2018;Seltzsam et al, 2022;van der Ven, Connaughton, et al, 2018;Weber et al, 2006). This percentages increases in the presence of extra-renal features of disease and in patients with so-called syndromic CAKUT.…”

“…In a Korean population of children with CAKUT, targeted exome sequencing identified genetic causes for 13.8% of the 94 pathogenic variants in either HNF1B , PAX2 , EYA1 , UPK3A , and FRAS1 (Ahn et al, 2020). More recently, we demonstrated that in a large cohort of 731 families with CAKUT, a single‐gene cause for CAKUT was identified in 11.4% of families (Seltzsam et al, 2022). Copy number variants (CNVs) result from either deletions or duplications of chromosomal regions.…”

“…In a heterogeneous pediatric cohort of 232 families encompassing a variety of subtypes of CAKUT, monogenic causation was observed in T A B L E 2 45 genes that represent monogenic causes of human isolated CAKUT, if mutated. (Sorted alphabetically by mode of inheritance) families (Seltzsam et al, 2022). Copy number variants (CNVs) result from either deletions or duplications of chromosomal regions.…”

Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome

“…Reverse genetics (i.e., reframing clinical diagnosis in view of genetic results) and identification of phenocopies have already proved efficacious in guiding this process in other fields of nephrology (e.g., podocytopathies and steroid-resistant nephrotic syndrome, ciliopathies, congenital anomalies of the kidney and urinary tract, etc.) [ 33 , 34 , 35 ], paving the way for a profound revision of disease ontology. Previous studies reported on disease reclassification based on reverse genetics, including in tubulopathies [ 14 , 18 , 28 , 36 ].…”

Angeborene Fehlbildungen von Nieren und Harntrakt (CAKUT)

“…Denn sie ermöglicht ein Reverse-Phenotyping und so ein gezieltes Suchen nach syndromaler Beteiligung. Beispielsweise könnte so aus einer „unspezifischen fokal-segmentalen Glomerulosklerose (FSGS)“ eine „ PAX2 -assoziierte Nephropathie mit Netzhautkolobom“ werden, was die klinische Versorgung entsprechend verändert und die Prognose nach Nierentransplantation deutlich verbessert 7 , 8 .…”