The dark side of carrier screening: illuminating hard-to-decipher genes in common genetic disorders

Carrier screening (CS) aims to identify couples at risk for having a child with a severe genetic disorder. Although next-generation sequencing (NGS) is a widely used method, it fails to resolve many problematic genes, such as those with tandem repeats, copy number variation, pseudogenes, and structural variation. These genes require multiple specialized techniques and only cover a fraction of carrier risk. We combined three innovations to address these shortcomings: novel long-range PCR enrichment, nanopore sequencing, and companion bioinformatic software. Using a single workstream, we developed a prototype assay panel of 11 genes critical for CS, including eight “hard-to-decipher” genes, representing ~70% of all pathogenic variants for a severe inherited disorder in at-risk couples compared to gene panels at least 15 times larger. We describe evaluation of this prototype assay for CFTR, SMN1, SMN2, FMR1, HBA1, HBA2, HBB, F8, GBA, CYP21A2, and TNXB across 380 samples.

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