Abstract
The Viking Health Study Shetland is a population-based research cohort of 2,122 volunteer participants with ancestry from the Shetland Isles in northern Scotland. The high kinship and detailed phenotype data support a range of approaches for associating rare genetic variants, enriched in this isolate population, with quantitative traits and diseases. As an exemplar, the c.1750G > A; p.Gly584Ser variant within the coding sequence of the KCNH2 gene implicated in Long QT Syndrome (LQTS), which occurred once in 500 whole genome sequences from this population, was investigated. Targeted sequencing of the KCNH2 gene in family members of the initial participant confirmed the presence of the sequence variant and identified two further members of the same family pedigree who shared the variant. Investigation of these three related participants for whom single nucleotide polymorphism (SNP) array genotypes were available allowed a unique shared haplotype of 1.22 Mb to be defined around this locus. Searching across the full cohort for this haplotype uncovered two additional apparently unrelated individuals with no known genealogical connection to the original kindred. All five participants with the defined haplotype were shown to share the rare variant by targeted Sanger sequencing. If this result were verified in a healthcare setting, it would be considered clinically actionable, and has been actioned in relatives ascertained independently through clinical presentation. The General Practitioners of four study participants with the rare variant were alerted to the research findings by letters outlining the phenotype (prolonged electrocardiographic QTc interval). A lack of detectable haplotype sharing between c.1750G > A; p.Gly584Ser chromosomes from previously reported individuals from Finland and those in this study from Shetland suggests that this mutation has arisen more than once in human history. This study showcases the potential value of isolate population-based research resources for genomic medicine. It also illustrates some challenges around communication of actionable findings in research participants in this context.
Highlights
The Northern Isles of Scotland (Orkney and Shetland) have been isolated from the rest of the British Isles by their extreme northern geographic position and this isolation is reflected in substantial population genetic structuring both within and between these archipelagos and mainland Britain[1,2,3,4]
Detection of a Long QT Syndrome (LQTS) rare variant. 500 whole genomes of VIKING participants were sequenced to high depth
These whole genome sequencing (WGS) data add to the genome-wide genotype and deep phenotype data, which are available on this research cohort of more than 2,000 people with Shetlandic ancestry
Summary
The Northern Isles of Scotland (Orkney and Shetland) have been isolated from the rest of the British Isles by their extreme northern geographic position and this isolation is reflected in substantial population genetic structuring both within and between these archipelagos and mainland Britain[1,2,3,4]. During the recruitment of volunteers to the VIKING Study, one participant offered the research team a letter s/he had received from the local regional genetic service which informed him/her of a familial risk of long QT syndrome and detailed the causative actionable variant. This is c.1750G > A; p.Gly584Ser in the KCNH2 gene, which encodes a potassium channel in which this variant causes abnormal inactivation gating[17]. These data facilitated genomic analyses, allowing determination of whether any participants with this actionable variant were present in the entire VIKING cohort
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