Following the forensic investigation and molecular autopsy performed on an 18-year-old female who died suddenly and unexpectedly, a co-segregation family study was conducted of the first-degree relatives, and functional characterization of the variant were conducted.
Molecular testing of the deceased (Molecular Autopsy) is an overlooked area in the United States healthcare system and is not covered by medical insurance, leading to ineffective care for surviving families of thousands of sudden unexpected natural deaths each year. The current study demonstrated the precision management of surviving family members through the discovery of a novel de novo pathogenic variant in a decedent. The molecular autopsy identified a novel nonsense variant, NP_000229.1:p.Gln1068Ter, in the long QT syndrome type II gene KCNH2 in the decedent. This finding correlated with her ante-mortem electrocardiograms. Patch clamp functional studies using transfected COS-7 cells show that hERG-ÄQ1068 has a mixed phenotype, with both gain- (negative voltage shift of steady-state activation curve, the positive shift of the steady-state inactivation curve, and accelerated activation) and loss-of function (reduced current density, reduced surface expression and accelerated deactivation) hallmarks. Loss of cumulative activation during rapid pacing demonstrates that the loss-of-function phenotype predominates. The wild-type channel did not rescue the hERG-ÄQ1068 defects, demonstrating haploinsufficiency of the heterozygous state. Targeted variant testing in the family showed that the variant in KCNH2 arose de novo, which eliminated the need for exhaustive genome testing and annual cardiac follow-up for the parents and four siblings. The study concludes that molecular testing enables accurate determination of natural causes of death and precision care of the surviving family members in a time and cost-saving manner. The authors argue for molecular autopsy being included under healthcare insurance coverage in United States. (publisher abstract modified)