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

AI SUMMARY

FIDELITY 100%

POPULATION100 mostly sporadic patients with congenital anomalies of the kidney and urinary tract (CAKUT) diagnosed in the first 1000 days of life, with CKD stages 1 to 5D/T

INTERVENTIONWhole exome sequencing (WES) with analysis of 58 established CAKUT-associated genes

COMPARISONPatients requiring vs. not requiring kidney replacement therapy (KRT) before age 3; patients with vs. without extrarenal features

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TL;DR

Whole exome sequencing identified a likely pathogenic or pathogenic variant in 25% of 100 mostly sporadic CAKUT patients diagnosed before age 3, with significantly higher yields in those requiring kidney replacement therapy (43%) or having extrarenal features (41%). Genetic diagnosis enabled early detection and management of treatable comorbidities such as diabetes, hyperuricemia, hypomagnesemia, and hypoparathyroidism in 25% of patients. These findings support early genetic testing in selected CAKUT cohorts to improve clinical outcomes.

Full summary

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**Background:** Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of chronic kidney disease (CKD) and kidney replacement therapy (KRT) in children. Although over 60 genes are known to cause CAKUT, genetic etiology is detected in only about 16% of unselected cases. The authors hypothesized that the diagnostic yield may be higher in infants diagnosed with CAKUT, especially those requiring KRT before age 3. This study aimed to apply whole exome sequencing (WES) in a cohort of mostly sporadic CAKUT patients diagnosed in the first 1000 days of life and assess the translational value of genetic findings.

**Methods:** A total of 100 index cases (54% male, 46% female) with CAKUT including kidney involvement, diagnosed in the first 1000 days of life, were enrolled from Hannover, Germany and Oslo, Norway. Patients had unilateral (31%) or bilateral (69%) CAKUT. Only 6% had a positive family history. WES was performed on leukocyte DNA using SureSelectXT enrichment kits and HiSeq sequencers (mean target coverage 50×). Variants in 58 established CAKUT-associated genes were extracted and classified according to ACMG/AMP guidelines. Copy number variations (CNVs) were analyzed for 8 genes. Statistical analyses used Fisher exact test (2-tailed), with P < 0.05 considered significant.

**Key Results:** WES identified 27 likely pathogenic (LP) or pathogenic (P) variants in 25 of 100 patients (25% diagnostic yield). Variants were found in 15 of 58 CAKUT-associated genes, most frequently HNF1B and SIX2 (4 cases each), and GDF6, LIFR, PAX2, SALL1, TBC1D1, and UMOD (2 cases each). Of the 27 variants, 52% were loss-of-function (5 stop gain, 7 frameshift, 1 splicing, 1 whole-gene deletion) and 48% were missense. Inheritance was maternal in 11, paternal in 6, de novo in 5 (18.5%), and undetermined in 5. Two patients had LP/P variants in two genes, suggesting digenic inheritance. The diagnostic yield was significantly higher in patients requiring KRT before age 3 (9/21, 43%) vs. those not requiring KRT (16/79, 20%; odds ratio 2.95, P = 0.047). Similarly, yield was higher in patients with extrarenal features (14/34, 41%) vs. those without (11/66, 17%; odds ratio 3.5, P = 0.0136). In familial cases, yield was 83% (5/6) vs. 21% (20/94) in sporadic cases (P = 0.0035). Reverse phenotyping based on genetic findings led to diagnosis of treatable conditions: hyperuricemia in a UMOD carrier (age 11), elevated liver enzymes and hypomagnesemia in an HNF1B carrier (age 22), hyperuricemia in another HNF1B carrier (age 14), insulin resistance/prediabetes in a TBC1D1 carrier (age 17), and hypoparathyroidism in a GATA3 carrier (age 6). Overall, genetic diagnosis allowed preventive measures and/or early treatment in 25% of patients.

**Clinical Implications:** This study demonstrates that WES in CAKUT patients diagnosed in the first 1000 days of life yields a genetic diagnosis in 25% of cases, rising to 41-43% in those with extrarenal features or early KRT. The identification of LP/P variants in genes associated with extrarenal complications (e.g., HNF1B, UMOD, TBC1D1, GATA3) enables targeted surveillance and early management of comorbidities such as diabetes, hyperuricemia, hypomagnesemia, and hypoparathyroidism. The findings support early genetic testing in selected CAKUT cohorts to improve clinical outcomes through personalized monitoring and treatment.

PICO

PPOPULATION

100 mostly sporadic patients with congenital anomalies of the kidney and urinary tract (CAKUT) diagnosed in the first 1000 days of life, with CKD stages 1 to 5D/T

IINTERVENTION

Whole exome sequencing (WES) with analysis of 58 established CAKUT-associated genes

OOUTCOME

Diagnostic yield of likely pathogenic/pathogenic variants; odds ratios for yield in subgroups; translational impact (preventive measures/early treatment)

STUDY TYPE

cohort

SPECIALTY

pediatric ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

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