The Dark Side of Carrier Screening: Illuminating Hard-to- Decipher Genetic Variation with Nanopore Sequencing

Cystic Fibrosis (CF), Spinal Muscular Atrophy (SMA), Hemoglobinopathies, and Fragile X Syndrome (FXS) are among the most commonly inherited genetic disorders, each with high carrier rates that often require distinct genotyping methods.

High-prevalence carrier genes, associated with disorders such as Gaucher Disease (GD), congenital adrenal hyperplasia (21-OHD CAH), and Hemophilia A (HA), include complex structural variants and pseudogenes that confound conventional sequencing methods.

We explored whether novel PCR enrichment, nanopore sequencing, and machine learning models could detect multiple classes of variants including SNVs, INDELs, Exon del/dups, SVs, CNVs and STRs in a single workflow.

The assay was optimized with 168 cell-line samples and independently evaluated with 249 whole blood samples across the seven genes to identify potential carriers from presumed normal donors.

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