Low-depth whole genome sequencing as a complementary approach for detecting clinically relevant variants in hearing loss

Whole genome sequencing (WGS) enables comprehensive detection of coding and noncoding variants but routine implementation of standard-depth WGS (30x) remains constrained by sequencing cost and analytical burden. Here, we evaluate the analytical performance and clinical potential of low-depth WGS (10x) in individuals with hearing loss. The Genome Analysis Toolkit (GATK) and Dynamic Read Analysis for GENomics (DRAGEN) pipelines were compared at both sequencing depths. DRAGEN showed more consistent performance across single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants and was therefore selected for downstream analyses. In independent 10 × and 30 × cohorts, 30 × WGS yielded higher variant counts across most evaluated categories, whereas aggregate counts of exonic and splice-region variants in hearing-loss and secondary-finding genes were not significantly different. Six individuals were additionally sequenced at both depths for direct within-individual comparison. Aggregate counts of high-confidence SNVs and indels did not differ significantly, although 30 × WGS generally yielded numerically higher counts. All previously reported causal or clinically relevant variants identified in these individuals were detected at both depths. In addition, 10 × WGS detected clinically relevant structural variants and pathogenic mitochondrial variants evaluated in the study cohort. These findings suggest that 10 × WGS can detect many clinically relevant germline variants across diverse variant classes, particularly in analyses focused on established disease-associated genes. Low-depth WGS may therefore provide a lower-cost complementary strategy for selected clinical applications requiring genome-wide interrogation beyond the scope of exome sequencing.