Abstract
Modern genomic diagnostics are a powerful set of clinical tools, but their utilisation has potential for optimisation in Māori and Pacific populations. This study pioneered a method to disentangle the relative contributions of true and artefactual homozygosity identified by chromosomal microarray (CMA), aiming to understand how current CMA protocols serve Polynesian populations and what factors influencing this require future consideration. A sliding window-based approach was developed, using matched whole genome sequencing (WGS) data to closely interrogate the CMA-identified homozygosity, beginning with several case studies of rare disease to demonstrate the utility of WGS in a diagnostic context. This method allowed for high-resolution discernment of truly homozygous and artefactual regions by comparing the homozygosity identified by WGS and CMA. To show the utility of this method, a preliminary cohort of four Polynesian individuals and one non-Polynesian individual was analysed. In the Polynesian individuals, there was > 100 Mb of true homozygosity not identified by CMA, while ~50% of CMA-identified homozygosity was artefactual. Application of this method and findings to a larger cohort of matched CMA and WGS data is needed to fully disentangle the state of homozygosity in Polynesian people and its effect on autosomal recessive Mendelian disease prevalence. This research has begun paving the way for optimising clinical outcomes for Māori and Pacific patients, implementing WGS in an innovative, novel fashion to explore a potential inequity.