Masterclass 10 - Sudden Death Prevention in the Young - Molecular Autopsy and Familial Screening Service

In this presentation, Dr Lai will give an overview on the legal framework and interdepartmental procedures involved in the investigation of Coroner's cases in Hong Kong, with special reference to sudden death cases. The work of forensic pathologists at the scene, post-mortem examination, post-mortem imaging, forensic autopsy, interpretation of laboratory findings in post-mortem samples, and counselling for the next of kin will be briefly discussed. Colleagues in the fields of emergency medicine, cardiology, paediatrics and anatomical pathology may found this presentation particularly useful.

Molecular autopsy investigations have revolutionized the laboratory approach to understanding the causes of sudden death in both children and adults. This process leverages advanced genomic technologies to uncover metabolic and genetic factors that may have contributed to these unexpected fatalities. In the laboratory setting, the integration of high-throughput sequencing techniques, such as next-generation sequencing (NGS), allows for the comprehensive analysis of genetic variants associated with sudden death.
In pediatric cases, metabolic disorders, including urea cycle defects and mitochondrial dysfunction, often remain undiagnosed prior to death. Laboratory investigations focus on identifying biochemical markers and genetic mutations that could indicate these conditions. In adults, inherited cardiomyopathies and channelopathies frequently necessitate thorough genetic screening to pinpoint pathogenic variants.
Collaboration between laboratory professionals and clinical specialists is essential for effective molecular autopsy investigations. Forensic pathologists ensure proper sample collection and preservation, determining when molecular and metabolic autopsy investigations are necessary based on suggestive findings indicating underlying genetic or metabolic conditions. Meanwhile, chemical and genetic pathologists conduct detailed analyses of DNA, RNA, and metabolites to uncover potential contributing factors to sudden death. This teamwork enhances the quality of data generated and facilitates accurate diagnoses.
Furthermore, the application of bioinformatics tools aids in interpreting complex genomic data, allowing for the identification of rare variants with potential clinical significance. The identification of these variants not only informs individual cases but also contributes to broader epidemiological insights into sudden death.
Ultimately, molecular autopsy investigations from a laboratory perspective provide critical insights into the genetic and metabolic underpinnings of sudden death. By bridging clinical findings with laboratory data, these investigations pave the way for improved diagnostic accuracy, familial screening, and preventive strategies aimed at reducing the incidence of unexplained fatalities. This integrated laboratory approach is vital for advancing our understanding of sudden death and enhancing patient care.

Sudden cardiac death refers to the unexpected death of an individual due to an underlying cardiac disease occurring within one hour of onset of symptoms in an apparently healthy subject or, if unwitnessed, in someone known to be in good health up to 24 h before the event. In literature Sudden Cardiac Death accounts for around 15–20% of all deaths in the general population.
In young subjects, Sudden cardiac death is usually a fatal complication of cardiomyopathies or channelopathies. In this Talk, the basic genomics of inherited cardiomyopathies and channelopathies will be shared. The principle of genetic counselling on Sudden cardiac death has also be discussed. 

Sudden cardiac death (SCD) remains a significant public health challenge, often occurring without prior symptoms and disproportionately affecting younger individuals, leaving families profoundly impacted. Emerging evidence highlights a substantial genetic underpinning, emphasizing the crucial role of familial evaluation and precision medicine in mitigating risk and improving outcomes. 


This talk addresses recent advances in precision medicine approaches to SCD. We will explore how genetic testing facilitates early identification of at-risk individuals, enabling targeted preventive interventions, lifestyle modifications, and timely clinical management.  With availability of molecular autopsy services since 2017, cascade genetic testings are offered to family members if pathogenic variants are identified in SCD victims. However, there have been a low compliance to clinical screening attended by the affected first-degree relatives. It could be due to a lack of family awareness regarding the potential inheritance of diseases and availability of cardiovascular screening service. Combining the yield of clinical screening in a multidisciplinary setting, the yield of inheritable cardiovascular condition can be up to 45%. The phenotype information is also crucial in assisting with the pathogenicity determination of identified SCD genetic variants. 


The talk will illustrate how personalized risk stratification and tailored clinical interventions significantly reduce the burden and recurrence of sudden cardiac death within families. It is important as broader public health implications in reducing SCD incidence. This presentation seeks to enhance clinicians' understanding of precision medicine's transformative potential in familial evaluation, empowering healthcare professionals to deliver personalized, proactive cardiac care, and understanding of the need for multidisciplinary effort in service deliverance.