NCM 2023 Singapore: Comprehensive structural and copy number variant detection: from mosaic to population-level

Understanding the mechanism behind human diseases with an established heritable component is the next frontier in personalized medicine. Furthermore, understanding how these mechanisms may vary across ethnicities is crucial for accurate genetic risk prediction in the clinic. To respond to these challenges, we are leveraging Oxford Nanopore technology to discover germline and mosaic variation at scale and with accuracy. Our latest release on Sniffles and Spectra includes novel methods to improve detection of structural and copy number variation across hundreds of individuals. Furthermore, Sniffles2 solves the problem of family- to population-level SV calling to produce fully genotyped VCF files by introducing a gVCF file concept. Across 11 probands, we accurately identified causative SVs around MECP2, including highly complex alleles with three overlapping SVs. Sniffles2 also enables the detection of mosaic SVs in bulk long-read data. As a result, we successfully identified multiple mosaic SVs across a multiple-system-atrophy patient brain. The identified SV showed a remarkable diversity within the cingulate cortex, impacting both genes involved in neuron function and repetitive elements. In my presentation I will outline the novel updates on Sniffles and Spectra to further improve the detection of variants utilizing nanopore sequencing. These updates include improved tumour-normal comparisons, mosaic SV discovery and improvements to population sequencing. Overall, the continuous advancement of our methods coupled with the scale of Oxford Nanopore sequencing at Baylor College of Medicine and worldwide are the steppingstones to improve disease discovery and personalized medicine.