The uncertainty of causes of sudden cardiac death: the promising role of the molecular autopsy and family screening to weight scientific evidence

In sudden cardiac deaths (SCD), the identification of the cause(s) of death at autopsy may be challenging, especially in some conditions where the border between physiological and pathological changes is not defined. This paper describes a case of SCD in an 18-month-old child with two abnormalities of uncertain significance. The multi-disciplinary approach included PMCT, autopsy, histological, toxicological and genetic analysis. Parental screening and targeted genetic testing were performed. Two potentially pathogenic abnormalities were detected: a high take-off origin of the left coronary artery from the tubular aorta and a heterozygous variant, harbored by the mother and the grandfather, within exon 1 of the KCNQ1 (potassium voltage-gated channel subfamily Q member 1) gene (p.Ala46Thr). The clinical examination, basal ECG and Holter ECG were normal, except for a single borderline QTc interval measurement in the mother. The high coronary origin is classified by the International Guidelines for autopsy investigation in SCD as an “uncertain” cause of death and the genetic variant is classified as of “uncertain” or “likely pathogenic” significance in Clinvar and Varsome, respectively. The possibility to perform an extended family screening revealed the lack of a solid genotype-phenotype correlation, and the KCNQ1 variant cannot with any certainty be regarded as disease-causing. When autopsy findings fall into the grey zone between physiological and pathological changes, as well as post-mortem genetic analysis, the standardized clinical testing of families should be emphasized in order to understand the role of gene variants, and to produce evidences for the realization of personalized medicine.