Abstract
Abstract 12260: Whole Exome Molecular Autopsy With Copy Number Variant Analysis of Multiple Autopsy Negative Sudden Unexplained Deaths Among Amish Siblings Yields the Discovery of a Novel Homozygous Multi-exon Duplication in the Ryr2-Encoded Ryanodine Receptor
Circulation (New York, N.Y.), Vol.140(Suppl_1 Suppl 1), pp.A12260-A12260
11/19/2019
DOI: 10.1161/circ.140.suppl_1.12260
Abstract
BackgroundThe whole exome molecular autopsy (WEMA) may elucidate a pathogenic substrate for sudden unexplained death in the young (SUDY). We combined the WEMA with copy number variant (CNV) analysis to identify the underlying cause for multiple SUDYs and sudden cardiac arrests (SCAs) that occurred in two large Amish pedigrees.MethodsAn Amish family with exercise-associated SUDY occurring in 4 siblings was referred for a WEMA. A recessive inheritance pattern was suggested based on an extended family history of SUDY/SCA despite unaffected parents. CNV analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide breakpoints of the CNV were determined by mate pair sequencing (MPseq).ResultsA homozygous tandem duplication- involving ~26,000 base-pairs of intergenic sequence, involving RYR2’s 5’UTR/promoter region and exons 1-4 of RYR2, was identified in all 4 siblings. Multiple distantly related relatives experiencing exertion-related SCA also hosted the identical RYR2 homozygous duplication. A second Amish pedigree with multiple exertion-related SCA/SUDY hosting the same homozygous duplication was also identified. Several living, homozygous duplication-positive symptomatic patients from both pedigrees had a non-diagnostic stress test with only occasional ventricular ectopy.ConclusionHere, we identified a novel homozygous multi-exon duplication in RYR2 that is responsible for highly penetrant, multiple exertion-related SUDYs/SCAs occurring in the Amish community without an overt phenotype to suggest 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.
Details
- Title: Subtitle
- Abstract 12260: Whole Exome Molecular Autopsy With Copy Number Variant Analysis of Multiple Autopsy Negative Sudden Unexplained Deaths Among Amish Siblings Yields the Discovery of a Novel Homozygous Multi-exon Duplication in the Ryr2-Encoded Ryanodine Receptor
- Creators
- David Tester - Mayo ClinicHannah Bombei - University of IowaKristi Fitzgerald - DuPontJohn Giudicessi - Mayo Clinic in FloridaBeth Pitel - Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MNErik Thorland - Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MNBarbara Russell - Universidade Lusófona do PortoSamantha Hamrick - Mayo ClinicC S Kim - Mayo ClinicCarla Haglund-Turnquist - Mayo ClinicChristopher Johnsrude - University of LouisvilleDianne Atkins - University of IowaLuis Ochoa - University of IowaIan Law - University of IowaJoel Temple - DuPontMichael Ackerman - Mayo Clinic
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.140(Suppl_1 Suppl 1), pp.A12260-A12260
- Publisher
- by the American College of Cardiology Foundation and the American Heart Association, Inc
- DOI
- 10.1161/circ.140.suppl_1.12260
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/19/2019
- Academic Unit
- Stead Family Department of Pediatrics; Cardiology
- Record Identifier
- 9984354385002771
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