Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community.

Key PointsQuestionWhat is the underlying genetic cause of multiple sudden deaths in young individuals and sudden cardiac arrests observed in 2 large Amish extended families? FindingsIn this molecular autopsy and genetic analysis, a novel homozygous multiexon duplication in RYR2 was identified among young Amish individuals with exertion-related sudden deaths and sudden cardiac arrests without an overt phenotype to suggest RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. MeaningConsidering that no cardiac tests reliably identify at-risk individuals, and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning. ImportanceThe exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death. ObjectiveTo investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac arrests that occurred in 2 large Amish families. Design, Setting, and ParticipantsTwo large extended Amish families with multiple sudden deaths in young individuals and sudden cardiac arrests were included in the study. A recessive inheritance pattern was suggested based on an extended family history of sudden deaths in young individuals and sudden cardiac arrests, despite unaffected parents. A family with exercise-associated sudden deaths in young individuals occurring in 4 siblings was referred for postmortem genetic testing using an exome molecular autopsy. Copy number variant (CNV) analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide break points of the CNV were determined by mate-pair sequencing. Samples were collected for this study between November 2004 and June 2019. Main Outcomes and MeasuresThe identification of an underlying genetic cause for sudden deaths in young individuals and sudden cardiac arrests consistent with the recessive inheritance pattern observed in the families. ResultsA homozygous duplication, involving approximately 26000 base pairs of intergenic sequence, RYR2's 5UTR/promoter region, and exons 1 through 4 of RYR2, was identified in all 4 siblings of a family. Multiple distantly related relatives experiencing exertion-related sudden cardiac arrest also had the identical RYR2 homozygous duplication. A second, unrelated family with multiple exertion-related sudden deaths and sudden cardiac arrests in young individuals, with the same homozygous duplication, was identified. Several living, homozygous duplication-positive symptomatic patients from both families had nondiagnostic cardiologic testing, with only occasional ventricular ectopy occurring during exercise stress tests. Conclusions and RelevanceIn this analysis, we identified a novel, highly penetrant, homozygous multiexon duplication in RYR2 among Amish youths with exertion-related sudden death and sudden cardiac arrest but without an overt phenotype that is distinct from RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Considering that no cardiac tests reliably identify at-risk individuals and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning. This study investigates the underlying cause of multiple sudden deaths and sudden cardiac arrests that occurred in children of 2 large Amish families.