Structured Application of Nephrogenetics in a Pediatric Kidney Clinic Is Clinically Impactful and Challenging

Background: As clinical genetic testing becomes more accessible, their use as a diagnostic tool for kidney disease is becoming more common. While the utility of genetic testing has been described in adult nephrology clinics, its application and impact in pediatric kidney clinics is less clear. Methods: We retrospectively reviewed 10-years of clinical and genetic data on patients presenting to our pediatric kidney genetics program. The data analyzed includes genetic variants classified as pathogenic (P) or likely pathogenic (LP) by the ACMG criteria and their impact on clinical care. Details on genetic testing strategies and variants of uncertain significance (VUS) were collected. Results: Among 331 patients, with a mean age of 8.6 ± 6.7 years, N=166 (50%) received clinical genetic testing. Of these, 106/166 had informative genetic test results: 75% of which had a P or LP variant explaining their condition, while 25% had a P/LP variant non-explanatory for the kidney disease condition. Top genes with P/LP variants were PKD1 (N=16), PKHD1 (N=12, 11 were biallelic), TSC2 (N=11), HNF1B (N=9), AVPR2 (N=4). A carrier state unrelated to the kidney condition was reported in 28/166 patients, most commonly in APOL1 (N=9) and NPHS2 (N=4). A VUS was reported in 77/166 patients, with 49% of these having a VUS in ≥ 5 genes, most frequently in PKHD1 (N=15) and PKD1 (N=13). Testing strategies included a broad gene panel (>50 genes; N=40/166), limited gene panel (≤ 50 genes; N=49/166), exome sequencing (N=11/166), chromosomal microarray, (N=4/166) or combinations (N=13/166). Clinical impact measured for patients with P/LP variants included reclassification of diagnosis (38/106), disease-modifying therapy initiation (37/106), and avoidance of unnecessary procedures (22/106) and medications (44/106). Genetic results assisted in transplant evaluation (4/166), extra-renal screening (70/106), and reproductive counseling (42/106). Conclusion: In a select cohort of children referred to a kidney genetics program, genetic testing was used in 50% of cases and is clinically impactful in patients with a P/LP variant explaining the disease condition. Genetic variants not directly related to the disease condition are frequent and pose a challenge for interpretation and counseling.