Abstract
For breast and ovarian cancer risk assessment in the isolated populations of the Northern Isles of Orkney and Shetland (in Scotland, UK) and their diasporas, quantifying genetically drifted BRCA1 and BRCA2 pathogenic variants is important. Two actionable variants in these genes have reached much higher frequencies than in cosmopolitan UK populations. Here, we report a BRCA2 splice acceptor variant, c.517-2A>G, found in breast and ovarian cancer families from Shetland. We investigated the frequency and origin of this variant in a population-based research cohort of people of Shetland ancestry, VIKING I. The variant segregates with female breast and ovarian cancer in diagnosed cases and is classified as pathogenic. Exome sequence data from 2108 VIKING I participants with three or more Shetlandic grandparents was used to estimate the population prevalence of c.517-2A>G in Shetlanders. Nine VIKING I research volunteers carry this variant, on a shared haplotype (carrier frequency 0.4%). This frequency is ~130-fold higher than in UK Biobank, where the small group of carriers has a different haplotype. Records of birth, marriage and death indicate genealogical linkage of VIKING I carriers to a founder from the Isle of Whalsay, Shetland, similar to our observations for the BRCA1 founder variant c.5207T>C from Westray, Orkney. In total, 93.5% of pathogenic BRCA variant carriers in Northern Isles exomes are accounted for by these two drifted variants. We thus provide the scientific evidence of an opportunity for screening people of Orcadian and Shetlandic origins for each drifted pathogenic variant, particularly women with Westray or Whalsay ancestry.
| Original language | English |
|---|---|
| Pages (from-to) | 1624–1631 |
| Number of pages | 8 |
| Journal | European Journal of Human Genetics |
| Volume | 32 |
| Issue number | 12 |
| Early online date | 22 Oct 2024 |
| DOIs | |
| Publication status | Published - Dec 2024 |
Bibliographical note
The study team wish to thank staff from the NHS Grampian genetics team and the Viking Genes Study for their contribution to these datasets. DNA extractions were performed at the Edinburgh Clinical Research Facility, University of Edinburgh. Sanger sequencing was performed by Camilla Drake and the technical services team at the MRC HGU. Emily Weiss and Reka Nagy assembled the ORCADES pedigree, and Barbara Gray the Shetland pedigree, using records at the General Register Office and study information, building on earlier pedigree work by Ruth McQuillan and Jim Wilson. We thank Thibaud Boutin for phasing the GSA chip data and Kiera Johnston for help with analysis of other cancer susceptibility genes. The data in the EHR was provided by patients and collected by the NHS as part of their care and support. We would also like to acknowledge the invaluable contributions of the research nurses in Orkney and Shetland and the administrative team in Edinburgh, and the NHS Grampian genetic counselling team for counselling of the carriers identified in the cohorts. Finally, and most importantly, we thank the people of the Northern Isles for their involvement in and ongoing support for our research.Data Availability Statement
Data availabilityThere is neither Research Ethics Committee approval, nor consent from participants, to permit open release of the individual level research data underlying this study. The datasets generated and analysed during the current study are therefore not publicly available. Instead, the research data and/or DNA samples are available from [email protected] on reasonable request, via managed access, following approval by the Data Access Committee and in line with the consent given by participants.
Supplementary information: The online version contains supplementary material available at https://doi.org/10.1038/s41431-024-01704-w.
Funding
This work was funded by the MRC University Unit award to the MRC Human Genetics Unit, University of Edinburgh, MC_UU_00007/10 and a Wellcome Trust Institutional Translational Partnership Award (University of Edinburgh 222060/Z/20/Z -PIII031). LK was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1).
| Funders | Funder number |
|---|---|
| Medical Research Council | MC_UU_00007/10 |
| Wellcome Trust | 222060/Z/20/Z -PIII031 |
| UK Research and Innovation | MR/R026408/1 |
Access to Document
- Kerr_etal_EJHG_Two_Founder_Variants_VoR
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