Names of investigators
Jenefer M. Blackwell, Dave Tang, Timo Lassmann, Gareth Baynam, Sarra E. Jamieson, Richard Francis, Michelle Ward.
Project blurb
Rare diseases collectively affect >1 person in every 17. This equates to ~1.3 million Australians, including 400,000 children, living with a rare disease. Approximately 80% of all rare diseases have a genetic basis. Next generation sequencing allows partial or complete genomes to be sequenced at high speed and low cost. Whole exome sequencing (WES) (i.e. protein coding and adjacent regulatory sequences) has recently been implemented in WA as the diagnostic method of choice for rare diseases. As part of the TPHCRF collaborative project SeqNextGen (for “Sequence the Next Generation”), we have implemented a new pipeline to improve the rate of genetic diagnosis from the current 23% to 39% based on deeper interrogation of the genome. The pipeline is being refined to incorporate cellular and tissue-specificity for gene expression, and to allow interrogation of whole genome sequencing (WGS) data. Original aims of the project also included determining the clinical and social outcomes for patients and families receiving a diagnosis by WES. Questionnaires have been designed in consultation with epidemiologists, sociologists and consumer representatives on the project team. The evaluation project will take place following feedback of WES data to families taking part in the first phase of the SeqNextGen project. In 2016 we were also awarded funds under the Precision Medicine initiative to establish a functional validation pipeline using iPSCs and CRISPR-Cas9 gene editing techniques. This provides a form of ‘Koch’s postulate’ to validate genetic diagnoses: (i) to differentiate appropriate cell types from iPSCs and carry out functional studies relevant to the clinical phenotype and putative causative gene; (ii) to confirm that loss-of-function is returned to normal in the patient’s gene-edited cell line. Importantly, these transversal technologies can be used to investigate biological pathways and support therapeutic developments. This work is ongoing, with our ultimate goal being development and implementation of a person-centric Model of Care for people living with developmental anomalies and rare diseases in Western Australia.
Plain language summary
Rare diseases collectively affect >1 in 17 people. This equates to ~1.4 million Australians, including 500,000 children, living with a rare disease. ~80% of all rare diseases are genetic, characterized by increased rates of mortality, suffering, pain, frequently associated with intellectual impairment, a high burden for the child, family and the health system and often the uncertainty of a diagnostic odyssey. Just the 10 most prevalent single gene and chromosomal conditions in children account for 2.8% of all admissions to WA hospitals for children aged 0-19. These children have a higher number of admissions per patient, longer mean length of stay and an increased cost per admission compared to other children. This cohort accounted for 5.1% of the cost of hospital admissions of 0–19 year olds in this limited cohort in WA in 2006. Therefore, the early unambiguous diagnosis, enabled by Next Generation sequencing and functional validation of the genetic diagnosis, has the potential to enhance best practice and medical management, including genetic counselling, and also to provide efficiencies and savings to the health system.
Funders of the project
TPCHRF
Téa Lake and the Rare Disease Association Inc.
Office of Public Health Genomics, WA Health
Stan Perron Precision Medicine Award
External collaborators
Assoc Prof Richard Allcock (Head LotteryWest Sequencing Facility, UWA School Pathology & Laboratory Medicine)
Clin Assoc Prof Gareth Baynam (Clinical Geneticist, UWA and Murdoch University)
Adjunct Professor John Beilby (Head of Diagnostic Genomics, Pathwest Laboratories)
Ms Stephanie Broley (Genetic Counsellor, Genetic Services of WA)
Dr Mark Davies (Senior Medical Scientist, Diagnostic Genomics, Pathwest Laboratories)
Professor Hugh Dawkins (Head, Office of Public Health Genomics (OPHG), WA Health)
Ms Monique Garcia (WA Representative, Rare Voices Australia (RVA))
Dr Caroline Graham (Manager, OPHG, WA Health)
Prof Nigel Laing (Developmental Neurobiologist, Harry Perkins Institute for Medical Research)
Dr Caron Molster (Manager, Stakeholder and Community Engagement, OPHG, WA Health)
Associated Professor Nicholas Pachter (Director, Genetic Services of WA)
Dr Gina Ravenscroft (NHMRC Early Career Fellow, UWA Harry Perkins Institute for Medical Research)
Ms Amanda Samanek (Executive Director, Genetic and Rare Diseases Network (GARDN))
Dr Rachel Skoss (WA Register for Developmental Anomalies (WARDA) Consumer Group)
Prof Karen Simmer (Director, Neonatal Intensive Care Unit, KEMH/PMH)
Ms Michelle Ward (Genetic Counsellor, Genetic Services of WA)