Exome analysis–based molecular autopsy in cases of sudden unexplained death in the young

A Prospective Study of Sudden Cardiac Death among Children and Young Adults

“…18 The genetic analysis of DNA in cases of unexplained sudden cardiac death is summarized in Figure 1. In 51 of the 113 cases of unexplained sudden cardiac death (45%), we performed clinical-grade sequencing (i.e., a next-generation sequencing test accredited through the National Association of Testing Authorities) of the coding exons of 69, 98, or 101 cardiac disease genes on the Illumina MiSeq platform (Victorian Clinical Genetic Services).…”

“…16,17 Furthermore, population-based studies of human genetic variation have revealed an abundance of rare variants, which has led to increasingly stringent mutation classification criteria and a lower diagnostic yield of autopsy genetic testing for unexplained sudden cardiac death. 18,19 We performed a 3-year, prospective, population-based study of sudden cardiac death among persons 1 to 35 years of age in Australia and New Zealand and focused on determining the underlying cause of death after a comprehensive autopsy examination and genetic testing.…”

The ethics of conducting molecular autopsies in cases of sudden death in the young

“…In our study, we did not conduct validation testing of biological relatives, but as previous studies have confirmed, such validation testing and examination of family medical histories can help inform interpretation (Bagnall et al 2014;Miles and Behr 2016). For example, findings of a genetic variant in a clearly unaffected relative might signal caution, although because there is variable penetrance with many of these genes, causality would not be ruled out.…”

The role of genetic testing in unexplained sudden death

“…Advances in technology, massive parallel sequencing or next-generation sequencing, have led to the ability to simultaneously sequence protein coding exons of all genes nucleotide by nucleotide (''the exome,'' which is approximately 1% of the genome) from much smaller quantities of DNA. 128 Bagnall et al 125 performed exome sequencing on a subgroup of 28 SUDS cases referred for autopsy in Australia between 2005 and 2009. Three rare variants were discovered in the 3 most common LQTS genes when a narrow panel of the 4 major genes (KCNQ1, KCNH2, SCN5A, and RYR2) was studied.…”