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Sci Rep. 2019 Jul 29;9(1):10964. doi: 10.1038/s41598-019-47436-6.

An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort.

Author information

1
MRC Human Genetics Unit, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
2
Laboratory of Genetics, HUSLAB, Helsinki University Hospital, Helsinki, Finland.
3
Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
4
Heart and Lung Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
5
Edinburgh Genomics, The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Edinburgh, EH25 9RG, UK.
6
Medical Genetics Group, University of Aberdeen, Polwarth Building, Aberdeen, AB25 2ZD, UK.
7
Department of Medical Genetics, Ashgrove House, NHS Grampian, Aberdeen, AB25 2ZA, UK.
8
Centre for Genomic and Experimental Medicine, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK.
9
MRC Human Genetics Unit, University of Edinburgh, Institute of Genetics and Molecular Medicine, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. jim.wilson@ed.ac.uk.
10
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK. jim.wilson@ed.ac.uk.

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.

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