ABSTRACT
A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.
Subject(s)
Autopsy/methods , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/pathology , Pathology, Molecular/methods , Adolescent , Adult , Aged , Arrhythmogenic Right Ventricular Dysplasia/complications , Arrhythmogenic Right Ventricular Dysplasia/diagnosis , Arrhythmogenic Right Ventricular Dysplasia/genetics , Cardiomyopathies/complications , Cardiomyopathies/diagnosis , Cardiomyopathies/genetics , Cardiomyopathy, Dilated/complications , Cardiomyopathy, Dilated/diagnosis , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathy, Hypertrophic/genetics , Channelopathies/complications , Channelopathies/diagnosis , Channelopathies/genetics , Child , Child, Preschool , Female , Genetic Predisposition to Disease/genetics , Humans , Infant , Male , Middle Aged , Mutation , Phenotype , Young AdultABSTRACT
AIM: Recent events surrounding postmortem practices have necessitated several changes in the way necropsies are conducted both within the medicolegal and hospital settings. These changes have resulted in a striking reduction in the frequency of brain retention for neuropathological examination. Aberdeen Royal Infirmary, responding quickly to rising concerns among bereaved relatives regarding organ retention, instituted a change in practice regarding the examination of brains at necropsy as early as 2001. The new protocol involved subjecting the brain to rapid fixation using combined immersion and perfusion techniques. This allows return of the organ to the body without unreasonable delay to the funeral. In this article, we present the results of a retrospective audit comparing the efficacy of the new method against the conventional fixation protocol. METHODS: An equal number of postmortem brains were selected randomly from the year 1998 (following the usual fixation protocol), and from the year 2001 (following the new method). A three tier scoring system was devised to assess section and staining quality, and a single observer scored all the cases. RESULTS: No statistical difference was noted in the quality of sections prepared by rapid fixation those by conventional fixation. Furthermore, the rapid method was more frequently adequate for diagnosis (considering scores of 2 and 3 together) than the conventional method. CONCLUSION: Rapid fixation offers a viable alternative for detailed examination of brains at necropsy, without necessarily prolonging the retention of the organ.
