​​Feasibility study of resequencing and archival data reanalysis in 30 diagnosed trios from the Next Generation Children’s (NGC) Cohort ​

Summary

Rare genetic diseases, impacting around 3.5 million in the UK and 350-400 million worldwide, present considerable challenges to affected individuals, their families, and the healthcare system.

Family trio (child and biological parents) genetic testing involves analysing genes from affected child and both parents to identify potential genetic change(s) related to child’s symptoms. Recent advances in genetic diagnostic testing, using whole-genome sequencing (WGS) technology have significantly improved the diagnosis of rare diseases. In light of updates in genomic knowledge, technologies and databases, periodic reanalysis is essential for identifying new causative genetic variants to facilitate diagnosis and clinical care of patients.

The NIHR BioResource provides invaluable stored WGS data of the Cambridge Next Generation Children (NGC) study, consisting of NIHR Bioresource consented 521 families from Neonatal and Paediatric Intensive Care Units (NICU and PICU) and speciality clinics. This resource facilitates reanalysis and resequencing of stored whole genome sequencing (WGS) family trio data, with the aim to improve the diagnosis of undiagnosed patients using updated clinical data and the most recent analysis platforms and databases. This feasibility study aims to focus on a pilot-scale reanalysis of 30 family trios from the NGC cohort to address key issues related to reanalysis of both re-sequenced and stored WGS data. The primary objectives include comparing sequence quality of re-sequenced and stored WGS data, evaluating cost-effectiveness, and assessing the performance of analysis platforms for turnaround time, scalability, and accuracy. The resources, standard operating procedures, protocols, and results from this feasibility study will serve as valuable guidelines for implementing reanalysis strategies for diagnosis of undiagnosed patients in family trios. This study will inform large scale reanalysis of undiagnosed patient data in the NGC cohort.