TY - JOUR
T1 - Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system
T2 - implications for future testing
AU - Hocking, Lynne J.
AU - Andrews, Claire
AU - Armstrong, Christine
AU - Ansari, Morad
AU - Baty, David
AU - Berg, Jonathan
AU - Bradley, Therese
AU - Clark, Caroline
AU - Diamond, Austin
AU - Doherty, Jill
AU - Lampe, Anne
AU - McGowan, Ruth
AU - Moore, David J.
AU - O'Sullivan, Dawn
AU - Purvis, Andrew
AU - Santoyo-Lopez, Javier
AU - Westwood, Paul
AU - Abbott, Michael
AU - Williams, Nicola
AU - Aitman, Timothy J.
AU - Miedzybrodzka, Zosia
N1 - Funding Information:
The Scottish Genomes Partnership was funded by the Chief Scientist Office of the Scottish Government Health Directorates (SGP/1) and The Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure.
Copyright:
© 2022. The Author(s).
PY - 2023/2
Y1 - 2023/2
N2 - NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases - 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.
AB - NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases - 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.
KW - Diagnostic markers
KW - Genetics testing
KW - Health policy
UR - http://www.scopus.com/inward/record.url?scp=85143493136&partnerID=8YFLogxK
U2 - 10.1038/s41431-022-01226-3
DO - 10.1038/s41431-022-01226-3
M3 - Article
C2 - 36474026
SN - 1018-4813
VL - 31
SP - 231
EP - 238
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
ER -