Importance: The diagnosis and study of rare genetic disease is often limited to referral populations, leading to underdiagnosis and a biased assessment of penetrance and phenotype.
Objective: To develop a generalizable method of genotype inference based on distant relatedness and to deploy this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population.
Participants: We identified 9 LQT5 probands and 3 first-degree relatives referred to a single Genetic Arrhythmia clinic, each carrying D76N (p.Asp76Asn), the most common variant implicated in LQT5. The non-referral population consisted of 69,879 ancestry-matched subjects in BioVU, a large biobank that links electronic health records to dense array data. Participants were enrolled from 2007-2022. Data analysis was performed in 2022.
Exposures: We developed and applied a novel approach to genotype inference (Distant Relatedness for Identification and Variant Evaluation, or DRIVE) to identify shared, identical-by-descent (IBD) large chromosomal segments in array data.
Main outcomes and measures: We sought to establish genetic relatedness among the probands and to use genomic segments underlying D76N to identify other potential carriers in BioVU. We then further studied the role of D76N in LQT5 pathogenesis.
Results: Genetic reconstruction of pedigrees and distant relatedness detection among clinic probands using DRIVE revealed shared recent common ancestry and identified a single long shared haplotype. Interrogation of the non-referral population in BioVU identified a further 23 subjects sharing this haplotype, and sequencing confirmed D76N carrier status in 22, all previously undiagnosed with LQT5. The QTc was prolonged in D76N carriers compared to BioVU controls, with 40% penetrance of QTc ≥ 480 msec. Among D76N carriers, a QTc polygenic score was additively associated with QTc prolongation.
Conclusions and relevance: Detection of IBD shared chromosomal segments around D76N enabled identification of distantly related and previously undiagnosed rare-variant carriers, demonstrated the contribution of polygenic risk to monogenic disease penetrance, and further established LQT5 as a primary arrhythmia disorder. Analysis of shared chromosomal regions spanning disease-causing mutations can identify undiagnosed cases of genetic diseases.