Low-pass whole genome sequencing as a cost-effective alternative to chromosomal microarray analysis for low- and middle-income countries

Abstract

Abstract We recently demonstrated that low-pass whole-genome sequencing (LP-WGS) with 1x coverage is equally sensitive and specific as chromosome microarray analysis (CMA) for detecting copy number variants (CNVs). Although in Europe and USA the first-tier tests have already transitioned to whole-genome or exome sequencing, even CMA is still unavailable for approximately 71% of the Brazilian population, who exclusively rely on public health system (~ 140 million people). LP-WGS, costing only a quarter of CMA's price, presents a more economical, faster, and technically simpler alternative for detecting CNVs. In this study, we assessed the efficiency and reliability of LP-WGS as a more affordable alternative to CMA. A total of 1363 patients with unexplained neurodevelopmental delay/intellectual disability, autism spectrum disorders, and/or multiple congenital anomalies were enrolled. Those patients were referred from fifteen Nonprofit Organizations and University Centers located in different states in Brazil. The analysis of LP-WGS at 1x coverage (> 50kb) revealed a positive testing result in 22% of the cases (304/1363), in which 219 and 85 correspond to pathogenic/likely pathogenic (P/LP) CNVs and variants of uncertain significance (VUS), respectively. The 16% (219/1363) diagnostic yield observed in our cohort is comparable to the 15–20% reported for CMA in the literature. The use of commercial software, as demonstrated in this study, simplifies the implementation of the test in clinical settings. Particularly for countries like Brazil, where the cost of CMA presents a substantial barrier to most of the population, LP-WGS emerges as a cost-effective alternative for investigating copy number changes in cytogenetics.