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The Clinical Utility of Next-Generation Sequencing (NGS)-Based Genetic Testing in Pediatric Polycystic Kidney Disease 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
Polycystic kidney disease (PKD) in children shows broad genetic heterogeneity including forms such as ADPKD, ARPKD, and other ciliopathies, often making gene-specific testing inadequate and leading to missed diagnosis. Precise genetic identification in pediatric PKD is crucial for timely intervention and informed prognosis discussions, yet this remains challenging due to extensive genetic, allelic, and phenotypic variability within monogenic kidney diseases. In this study, we aimed to detect the effectiveness of next-generation sequencing (NGS)-based testing in diagnosing pediatric PKD, and to correlate genotype with phenotype.

Methods:
This prospective study, conducted from Jan 2020 to Jun 2024, included children under 18 with either (1) two or more bilateral kidney cysts without a family history of PKD, or (2) at least one cyst with a positive family history. Data were extracted from electronic medical records, and samples were collected from patients lacking clinical genetic testing or those with negative results that enabled research genetic testing, as well as, when possible, from family members.

Results:
We evaluated 109 patients (53.2% female), with a median age of 9 years (IQR, 0-13), from 99 families. Genetic testing was completed for 93 patients (84 families), while 6 patients are pending results, and 10 patients did not provide samples. Single pathogenic or likely pathogenic (P/LP) variants in dominant genes or two LP/P in recessive genes were initially identified in 65/93 patients (69.9%) and in 59/84 families (70.2%). The remaining 28 patients (25 families) were unresolved, with variants of uncertain significance (VUS) or benign changes detected. Segregation testing in relatives led to variant reclassification in 12/28 patients (9/25 families), resulting in a definitive genetic etiology identified in 77/93 patients (82.8%) from 68/84 families (80.9%).



Variants were identified in multiple genes, including monoallelic or copy number changes, with frequencies as follows: PKD1 (43%), PKD2 (7%), 17q12 deletion (7%), HNF1B (6%), NEK8 (4%), TSC2 (4%), TSC2-PKD1 (3%), PKHD1 monoallelic (3%), IFT140 (3%), GANAB (3%) and ZMYM2 (2%). Biallelic variants were identified in NPHP1 (4%) and TMEM67 (4%), and either biallelic (4%) or suspected biallelic (5%) variants in PKHD1 associated with ARPKD phenotypes.  Monoallelic, rare ADPKD gene variants in IFT140, GANAB, and PKHD1 (monoallelic), typically reported in adults, were found in our pediatrics cohort, alongside a novel ZMYM2 variant causing PKD.



Patients’ initial presentations were classified into four categories: symptomatic, incidental, prenatal detection, and family screening. Genetic testing yields were 100% for family screening, 83% for both prenatal detection and symptomatic presentations, and 76% for incidental cases. Intrauterine presentations (n=13) were linked to PKD1, HNF1B, 17q12 deletion, NEK8, TSC2/PKD1 deletion, and biallelic PKHD1. All cases with 17q12 deletion were identified prenatally, and one biallelic PKHD1 case was detected incidentally. PKD1 was present across all categories.



Among the 77 genetically resolved cases, 40 patients exhibited extrarenal manifestations, including cardiovascular, hepatobiliary, splenic, neurologic, dermatologic, ophthalmologic, behavioral, and developmental features. Genes associated with extrarenal manifestations included PKD1, PKD2, NEK8, NPHP1, 17q12 deletion, TSC2, PKHD1, ZMYM2, and TMEM67.

Conclusion:
The diagnostic yield of NGS-based genetic testing was high and genetically diverse; NGS is a powerful tool for detecting disease-causing genes in pediatric PKD. This methodology is also cost effective in comparison to other comprehensive genetic testing approaches such as whole genome sequencing.

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