Whole Exome Sequencing in Chinese Pediatric Patients With Nephrolithiasis

The incidence of pediatric nephrolithiasis has been increasing, and the role of genetic factors has garnered attention in recent years. This study aimed to explore the genetic basis underlying pediatric nephrolithiasis in Chinese population.

Whole exome sequencing (WES) was conducted in a consecutive cohort of 456 children over a 11-year period. Clinical and genetic data were systematically collected, analyzed, and comprehensively compared.

Average age was 4.2 years with a male-to-female ratio of 2.2. A total of 260 causative variants in 16 genes were identified in 141 children, resulting in a positive molecular diagnosis rate of 31%. Of the causative variants, 43% were novel. The most prevalent diagnoses were primary hyperoxaluria (PH) (AGXT: 20%, GRHPR: 11%, and HOGA1: 24%) and cystinuria (SLC3A1: 18% and SLC7A9: 14%). Children with positive molecular diagnoses were more likely to have stone episodes, bilateral stones, multiple stones, or nephrocalcinosis (all P < 0.05). Children with AGXT defects were more prone to have severe clinical manifestations, and those with HOGA1 defects and males with SLC3A1 and SLC7A9 defects tended to be diagnosed at a younger age. The concordance rate between suspected clinical diagnoses and molecular diagnoses was 81%. At least 29% of children could benefit from additional clinical advice based on a molecular diagnosis.

A genetic etiology was identified in 141 of 456 of pediatric patients (31%) with nephrolithiasis in a Chinese cohort. A positive molecular diagnosis is a risk factor for severe clinical presentation of pediatric nephrolithiasis. WES has the potential to be used to confirm or even modify clinical diagnoses, thereby facilitating individualized therapeutic and preventive interventions.