Genetic variants of uncertain significance: How to match scientific rigour and standard of proof in sudden cardiac death?

Simone Grassi; Oscar Campuzano; Mònica Coll; María Brión; Vincenzo Arena; Anna Iglesias; Ángel Carracedo; Ramon Brugada; Antonio Oliva

doi:10.1016/j.legalmed.2020.101712

Genetic variants of uncertain significance: How to match scientific rigour and standard of proof in sudden cardiac death?

Leg Med (Tokyo). 2020 Apr 23:45:101712. doi: 10.1016/j.legalmed.2020.101712. Online ahead of print.

Authors

Simone Grassi¹, Oscar Campuzano², Mònica Coll³, María Brión⁴, Vincenzo Arena⁵, Anna Iglesias³, Ángel Carracedo⁶, Ramon Brugada⁷, Antonio Oliva⁸

Affiliations

¹ Institute of Public Health, Section of Legal Medicine, Catholic University, Rome, Italy.
² Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Centro Investigación Biomédica Red Enfermedades Cardiovasculares, Madrid, Spain; Department of Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS, Barcelona, Spain.
³ Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
⁴ Genetics of Cardiovascular and Ophthalmological Diseases, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain; Genomic Medicine, University of Santiago de Compostela, IDIS, CIBERER, Santiago de Compostela, Spain.
⁵ Institute of Anatomical Pathology, Catholic University, Rome, Italy.
⁶ Genomic Medicine, University of Santiago de Compostela, IDIS, CIBERER, Santiago de Compostela, Spain.
⁷ Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Centro Investigación Biomédica Red Enfermedades Cardiovasculares, Madrid, Spain; Cardiology Service, Hospital Josep Trueta, Girona, Spain.
⁸ Institute of Public Health, Section of Legal Medicine, Catholic University, Rome, Italy. Electronic address: antonio.oliva@unicatt.it.

PMID: 32361481
DOI: 10.1016/j.legalmed.2020.101712

Abstract

In many SCD cases, in particular in pediatric age, autopsy can be completely negative and then a post-mortem genetic testing (molecular autopsy) is indicated. In NGS era finding new/rare variants is extremely frequent and, when only variants of unknown significance are found, molecular autopsy fails to find a cause of death. We describe the emblematic case of the sudden death of a 7-year-old girl. We performed a full-body micro-CT analysis, an accurate autopsy, a serum tryptase test and toxicological tests. Since the only macroscopic abnormality we found was a myocardial bridging (length: 1,1 cm, thickness: 0,5 cm) of the left anterior descending coronary artery, a molecular autopsy has been performed. NGS analysis on victim DNA detected rare variants in DPP6, MYH7, SCN2B and NOTCH1 and segregation analysis was then achieved. On the basis of ACMG/AMP (clinical) guidelines, all the found variants were classified as of unknown significance. In other words, both the macroscopic and genetic anomalies we found were of uncertain significance and then the autopsy failed to find the cause of the death. Our case raises three main discussion points: (a) economical, ethical and legal limitations of genetic investigation; (b) risk that genetic testing does not succeed in finding a certain cause of the death; (c) absence of specific guidelines to face the problem of VUS in forensic cases.

Keywords: Myocardial bridging; NGS; Pathologist responsibility; Sudden cardiac death; Unknown significance variants.