Abstract 12075: Whole-Genome Sequencing at 10-Days of Life in Perinatal Long-QT Syndrome Yields New Insights Into Disease Pathogenesis
Introduction: Perinatal LQTS represents a severe form of long-QT syndrome with poor outcomes and early genotype-specific treatment is limited by the 2 month turnaround time of standard panel genetic testing.
Hypothesis: We aimed to provide a molecular diagnosis within a clinically actionable timeframe.
Methods: We performed rapid CLIA-certified whole genome sequencing on two infants with perinatal long-QT syndrome delivering a molecular diagnosis at 10-days of life. Whole cell patch clamping and single cell genotyping were also performed.
Results: In Case #1 we discovered a previously characterized variant in KCNH2 which was paternally inherited, however whole genome sequencing provided an unbiased assessment of the entire catalog of human genes revealing a second maternally inherited modifier variant in RNF207.
In Case #2 we discovered a novel mutation leucine replacing valine (V1762L) at residue 1762 in the SNC5A sodium channel. Whole-cell patch clamping experiments show the V1762L mutation causes a profound defect in late sodium current ~4.5 fold greater than the wild-type channel. A single cell analysis demonstrated that the mutation was present in the genome of only 3 of 36 individually isolated and genotyped patient cells, suggesting mosaicism. Conspicuously, standard panel genetic testing was negative.
Conclusions: We report here the earliest molecular diagnoses of LQTS, and demonstrate that rapid whole genome sequencing may be fruitfully applied to perinatal LQTS. In case #1 we hypothesize that a polygenic inheritance may explain the early and severe perinatal presentation, and have identified a putative modifier gene for LQTS in RNF207. The observation of mosaicism in case #2 suggests that in studies of inherited disease, mosaicism represents a common mechanism by which causal variation may be missed.
Author Disclosures: J.R. Priest: None. C. Gawad: None. K. Kahlig: Employment; Significant; Personalis Inc.. S. Ceresnak: None. L. Malloy-Walton: None. K. Dunn: None. M.P. Grove: None. M. Perez: None. K. Maeda: None. A. Dubin: Other Research Support; Modest; Medtronic Corp. L. Belardinelli: Employment; Significant; Gilead Inc. R. Chen: Employment; Significant; Personalis Inc.. T. Quertermous: None. S. Quake: Ownership Interest; Significant; Fluidigm Inc. E.A. Ashley: Ownership Interest; Significant; Personalis Inc..
- © 2014 by American Heart Association, Inc.