Genomic variation detection in disease

Obtaining highly contiguous genome assemblies with Oxford Nanopore long-read sequencing enables the comprehensive investigation of disease-associated variants.

Approximately 20–30% of lung cancer patients remain undiagnosed with respect to their cancerous mutations; variant detection is particularly pressing in cases where an effective treatment remains elusive¹. Using PromethION whole-genome sequencing of cancer cell lines and lung cancer specimens, Sakamoto et al. identified a unique class of complex structural variant, consisting of copy number changes, inversions, and deletions, which could not be characterised using short-read sequencing¹. These variants were detected in six of the nine clinical research specimens analysed, and generally resulted in reduced gene expression levels and disruption of genes in the region. The authors concluded that these mutations may point to the causal mechanism of disease in individuals for whom this is unknown.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease which is difficult to identify ante-mortem due to its wide range of clinical manifestations; its genetic basis remains unsolved. Through PromethION whole-genome sequencing of NIID patients and their families, Jun Sone and colleagues identified a repeat expansion within the gene NOTCH2NLC which was consistently present in familial and sporadic cases of the disease but absent from all unaffected family members (Figure 1)². Using the Oxford Nanopore protocol for Cas9-mediated enrichment, the team subsequently enriched for the NOTCH2NLC repeat sequence to obtain higher read coverage at this locus and form a consensus; the results from this consensus analysis agreed well with their initial analysis of the whole-genome sequencing data.