Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life

Kidney International Reports · 14 authors, 9 centres

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The central result was a 25% diagnostic yield for likely pathogenic or pathogenic variants in known CAKUT genes.

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The central result was a 25% diagnostic yield for likely pathogenic or pathogenic variants in known CAKUT genes. The genetic diagnosis identified variants in genes like GATA3, HNF1B, LIFR, PAX2, SALL1, and TBC1D1, enabling preventive measures or early treatment for associated conditions (e.g., diabetes, hyperuricemia) in 25% of diagnosed patients. The findings suggest WES is particularly valuable for early, severe CAKUT cases, aiding in targeted management.

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cohort

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nephrology

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ORIGINAL PAPER

PMC10658255

Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life

Kidney International Reports

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ABSTRACT

Abstract Introduction Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause of chronic kidney disease (CKD) and the need for kidney replacement therapy (KRT) in children. Although more than 60 genes are known to cause CAKUT if mutated, genetic etiology is detected, on average, in only 16% of unselected CAKUT cases, making genetic testing unproductive. Methods Whole exome sequencing (WES) was performed in 100 patients with CAKUT diagnosed in the first 1000 days of life with CKD stages 1 to 5D/T. Variants in 58 established CAKUT-associated genes were extracted, classified according to the American College of Medical Genetics and Genomics guidelines, and their translational value was assessed. Results In 25% of these mostly sporadic patients with CAKUT, a rare likely pathogenic or pathogenic variant was identified in 1 or 2 of 15 CAKUT-associated genes, including GATA3 , HNF1B , LIFR , PAX2 , SALL1 , and TBC1D1 . Of the 27 variants detected, 52% were loss-of-function and 18.5% de novo variants. The diagnostic yield was significantly higher in patients requiring KRT before 3 years of age (43%, odds ratio 2.95) and in patients with extrarenal features (41%, odds ratio 3.5) compared with patients lacking these criteria. Considering that all affected genes were previously associated with extrarenal complications, including treatable conditions, such as diabetes, hyperuricemia, hypomagnesemia, and hypoparathyroidism, the genetic diagnosis allowed preventive measures and/or early treatment in 25% of patients. Conclusion WES offers significant advantages for the diagnosis and management of patients with CAKUT diagnosed before 3 years of age, especially in patients who require KRT or have extrarenal anomalies. Keywords: congenital anomalies of the kidney and urinary tract, extrarenal features, infancy, prevention, reverse phenotyping, whole exome sequencing

CITATION EXPORT

Lina Werfel, Helge Martens, Imke Hennies et al.. Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life. Kidney International Reports. (2023). https://doi.org/10.1016/j.ekir.2023.08.008

AUTHORS

14 · 9 CENTRES

Lina Werfel, Helge Martens, Imke Hennies, Ann Christin Gjerstad, Kerstin Fröde, Gheona Altarescu, Sushmita Banerjee, Irene Valenzuela Palafoll, Robert Geffers, Martin Kirschstein, Anne Christians, Anna Bjerre, Dieter Haffner, Ruthild G Weber

1Department of Human Genetics, Hannover Medical School, Hannover, Germany
2Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
3Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
4Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel
5Calcutta Medical Research Institute, Kolkata, India
6Department of Clinical and Molecular Genetics, Hospital Vall d’Hebron, Barcelona, Spain
7Genome Analytics Research Group, Helmholtz Center for Infection Research, Braunschweig, Germany
8Department of Pediatrics, General Hospital, Celle, Germany
9Center for Congenital Kidney Diseases, Center for Rare Diseases, Hannover Medical School, Hannover, Germany