Benchmarking Twist Genotyping-by-Sequencing Against Whole-Genome Sequencing in Nuclear Families

Genome-wide genotyping is widely used in human genetics research, and targeted sequencing-based approaches such as the Twist Bioscience genome-wide SNP capture platform (GxS) have emerged as alternatives to conventional SNP arrays. Here, we evaluated GxS genotype calls from 555 individuals in 184 nuclear families against matched whole-genome sequencing (WGS) calls and compared platform performance with that of the Illumina Infinium Global Screening Array-24 (GSA), which was evaluated in 987 individuals from 279 nuclear families. Genotype data were harmonized across platforms, and analyses were restricted to overlapping SNP loci. Across all callable positions, mean per-SNP call rates were 98.26% for GxS and 98.67% for GSA. Overall SNP concordance with WGS was 99.79% for GxS and 99.87% for GSA, and mean per-individual concordance was also 99.79% and 99.87%, respectively. Per-trio Mendelian violation rates of GxS are about 10 times those of WGS, while those of GSA are about 4 times those of WGS on average. These results indicate that GxS performs slightly worse than GSA by key concordance and inheritance metrics, while still showing strong overall agreement with WGS.