N-Care Project: using long-read sequencing for timely genetic diagnosis in critically ill infants across Asia-Pacific | LC26

Abstract
Conventional short-read sequencing (SRS) often fails to detect complex structural variants or methylation abnormalities. Long-read sequencing (LRS) provides comprehensive genome analysis with faster turnaround times, addressing these limitations. This study assesses the feasibility and clinical utility of Oxford Nanopore Technologies (ONT) LRS for molecular diagnosis in critically ill infants through a collaborative Asia-Pacific network. The Asia-Pacific Society of Human Genetics initiated the N-Care Project in February 2025 for infants under 18 months admitted to intensive care units. Eligible participants included those with syndromic features or meeting criteria for a brief resolved unexplained event (BRUE). Rapid singleton whole-genome sequencing was performed using ONT platforms at laboratories in Taiwan or Thailand. Among the first 28 cases, the diagnostic yield was 50% (14/28), with an average turnaround time of 4.98 ±1.84 days from sample arrival. Nine cases involved single nucleotide variants. Variants theoretically undetectable by short-read sequencing included phased compound heterozygous variants (n=2), structural variants (n=1), methylation abnormalities (n=1), and pseudogene copy number changes for spinal muscular atrophy (n=1). All diagnosed cases were clinically actionable, leading to specialist referral (n=8), targeted therapy adjustments (n=3), disease-specific surveillance (n=2), and palliative care (n=1). In conclusion, LRS enables the detection of a broad spectrum of genetic variants that are challenging to detect using SRS methods, with a rapid turnaround time, leading to changes in the management of critically ill infants. This study highlights its clinical utility and the importance of collaborative networks in improving access across resource-variable regions.

Biography
Dr Ni-Chung Lee (Nina) is a Pediatrician and a specialist in clinical genetics. She is the Clinical Professor at National Taiwan University Hospital and National Taiwan University Children’s Hospital. She received a Master’s degree at National Yang-Ming University and was trained in Pediatrics at Taipei Veterans General Hospital. She undertook a fellowship at the University of Florida and completed her PhD at the National Taiwan University. Nina has been interested in the molecular diagnosis for rare inherited metabolic diseases and congenital malformations. Her current research includes developing gene therapy for rare genetic disorders and molecular diagnosis for rare genetic syndromes.