Molecular autopsy: using the discovery of a novel de novo pathogenic variant in the KCNH2 gene to inform healthcare of surviving family
Jingyun Dong,
Nori Williams,
Marina Cerrone,
Christopher Borck,
Dawei Wang,
Bo Zhou,
Lucy S. Eng,
Ekaterina Subbotina,
Sung Yon Um,
Ying Lin,
Kevin Ruiter,
Lisa Rojas,
William A. Coetzee,
Barbara A. Sampson,
Yingying Tang
Affiliations
Jingyun Dong
Department of Pediatrics, NYU School of Medicine, USA; Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, USA; Department of Physiology and Neurosciences, NYU School of Medicine, USA
Nori Williams
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA
Marina Cerrone
Cardiovascular Genetics Program, Leon H Charney Division of Cardiology, NYU School of Medicine, NY, USA
Christopher Borck
Department of Pathology, New York City Office of Chief Medical Examiner, USA
Dawei Wang
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA
Bo Zhou
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA
Lucy S. Eng
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA
Ekaterina Subbotina
Department of Pediatrics, NYU School of Medicine, USA; Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, USA; Department of Physiology and Neurosciences, NYU School of Medicine, USA
Sung Yon Um
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA
Ying Lin
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA
Kevin Ruiter
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA
Lisa Rojas
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA
William A. Coetzee
Department of Pediatrics, NYU School of Medicine, USA; Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, USA; Department of Physiology and Neurosciences, NYU School of Medicine, USA
Barbara A. Sampson
Department of Pathology, New York City Office of Chief Medical Examiner, USA
Yingying Tang
Molecular Genetics Laboratory, New York City Office of Chief Medical Examiner, USA; Corresponding author.
Background: 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. We demonstrated the precision management of surviving family members through the discovery of a novel de novo pathogenic variant in a decedent. Methods: Forensic investigation and molecular autopsy were performed on an 18-year-old female who died suddenly and unexpectedly. Co-segregation family study of the first-degree relatives and functional characterization of the variant were conducted. Findings: We 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-ΔQ1068 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-ΔQ1068 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. Interpretation: 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. We advocate for molecular autopsy being included under the healthcare coverage in US.
