Fig. 1. Pedigrees of two unrelated families with a child who experienced fatal, nonanesthetic episodes. The haplotype was constructed on the basis of genotyping with microsatellite markers D19S191, D19S224, D19S220, and D19S47. The marker order is from centromere to telomere. The parentheses for the proband in family 1 indicate that the relative location of the 3983C haplotype is unknown. In family 2, the 3983C and 4505H variants were located on different alleles, and the R4505H variant was associated with the maternal 10–1–7–1 haplotype. Filled symbols with a bisecting line indicate individuals who died of a nonanesthetic episode; empty symbols represent clinically healthy family members. R or C = arginine or cysteine residue at position 3983; D or H = an aspartic acid or histidine residue at position 4505 (A) . Alignment of the region of ryanodine receptor (RYR) variants and flanking residues across species and RYR isoforms. The mutated residues are shown in bold. Nonconserved residues across RYR isoforms are shaded (B) .