Diagnostic Yield of Next-Generation Sequencing for Rare Pediatric Genetic Disorders: A Single-Center Experience.

Background

Next-generation sequencing (NGS), particularly whole-exome sequencing (WES), has become a powerful diagnostic tool for rare genetic conditions. However, its success rate varies based on the underlying genetic etiology and the population studied.

Methods

This retrospective study evaluated the diagnostic yield of NGS in a cohort of 137 pediatric patients with suspected rare genetic disorders in Bulgaria, a setting where such testing is not reimbursed and must be self-funded. The patients underwent either WES or targeted gene panel testing based on clinical presentation, family history, and genetic evaluation.

Results

The overall diagnostic yield was 45.99%, with WES achieving 51.25% and targeted testing achieving 38.60%. The highest yield was observed in patients presenting with both dysmorphic features and neurodevelopmental delays (62.5%), while the lowest was observed among those with isolated neurodevelopmental issues (10%). A significant portion of the identified variants (35.9%) were novel. Eight patients were diagnosed with copy number variants (CNVs) detected only through WES.

Conclusions

Our findings illustrate the value of WES as a first-line test and highlight the impact of deep phenotyping on diagnostic success. This study also emphasizes the need for a population-specific reference genome and equal access to genomic diagnostics in all European countries.