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.
A computational model of Purkinje fibre single cell electrophysiology: implications for the long QT syndrome