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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.
(460)| Volume 41, ISSUE 4, SUPPLEMENT , S200-S201, April 2022

Next-Generation Sequencing in Genetic Testing of Kazakhstani Sudden Cardiac Death Cases

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      Purpose

      The use of next-generation sequencing (NGS) enables a rapid analysis of many genes associated with sudden cardiac death (SCD). It is particularly useful in cases where traditional autopsy is negative or only shows non-diagnostic features, i.e., in sudden unexplained deaths (SUDs), which are often due to an underlying inherited arrhythmogenic cardiac disease. SCD most commonly occurs in patients with coronary heart disease, whereas inherited cardiomyopathies and primary electrical disorders prevail in younger SCD victims (up to 30% of all SCD in the young). The aim of the study was to elucidate the mutational spectrum in Kazakhstani SCD victims revealed by NGS of 96 genes associated with cardiac diseases and compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy.

      Methods

      We screened 37 suspected SCD cases (<45 years) using the customized HaloPlex Target Enrichment System (Agilent) and NGS for 96 genes associated with inherited cardiac syndromes and cardiomyopathies. 27 cases had non-diagnostic structural cardiac abnormalities and 10 cases, diagnosed with a cardiomyopathy post-mortem. ACMG/AMP guidelines were applied for variant interpretation of clinical significance.

      Results

      31 rare variants were identified in 17 (63%) of the deceased individuals with non-diagnostic structural cardiac abnormalities. Among them pathogenic variants in KCNQ1, KCNJ2, SCN5A, RYR2 genes were identified. The corresponding frequency in deceased individuals with cardiomyopathies was 35%. The most abundant mutations observed in MYBPC3, LAMA2, MYH6 and GAA.

      Conclusion

      Genetic screening revealed variants with likely functional effects at high rates, in 63% and 35% of the SCD cases with non-diagnostic and diagnostic cardiac abnormalities, respectively. Targeted NGS screening can support the forensic investigation and help the cardiologist's decision to offer counselling and clinical evaluation to relatives of young SCD victims. NGS has nonetheless brought new challenges to molecular autopsy, especially regarding the clinical interpretation of the large number of variants of unknown significance detected in each individual. Study was supported by a grant from the Ministry Education and Science, Republic of Kazakhstan (AP09563474).