Figure 1. Amish pedigrees with recessively inherited exertion-associated SUDY.

Shown are 2 unrelated Amish pedigrees (pedigree 1 and pedigree 2) (A) with autopsy-negative sudden unexplained deaths or cardiac arrests. Open symbols (circles, women and girls; squares, men and boys) represent unaffected individuals. Black symbols represent affected family members. The age (in years) at sudden death is provided below the symbol representing sex. The yellow circles represent those family members whose iPSC-CMs were available for study. The red circle indicates the sudden death victim whose heart tissue was available for study. (B) A representative Sanger sequencing chromatogram from one of the RYR2-duplicated (RYR2 Dup) iPSC clones hosting the homozygous duplication and a graphical representation of the biallelic tandem 344,085 base pair (bp) duplication involving approximately 26,000 bp of intergenic sequence, RYR2’s 5′ UTR/promoter region, and exons 1–4 of RYR2. (C) Bar graph illustrating the calculated copy number of RYR2 alleles in genomic DNA derived from patients known to be negative (WT, 2 copies), heterozygous (3 copies), or homozygous (4 copies) for the RYR2 duplication as well as confirmation of genotype in each control and mutant iPSC clone.