Discordance in Malignant Hyperthermia Testing

Discordance has confounded linkage analysis worldwide. Examples include IVCT-tested normal (MHN) patients carrying an RYR1 mutation or an IVCT-tested positive (MHS) patient who does not carry the familial RYR1 mutation. Several explanations are possible: inexact thresholds for the IVCT or CHCT leading to errors in determining MHN or MHS; variable penetrance; and other unknown genes or modifier genes. Robinson and associates demonstrated by the transmission disequilibrium test (TDT) that loci on chromosomes 5 and 7 and, to a lesser extent, loci on chromosomes 1 and 7 influence susceptibility to MH.^[32] A number of families have two RYR1 mutations on separate haplotypes.^[30] Because of discordance, it is not possible to exclude MH on the basis of genetic testing alone.^[33]

European Guidelines for Screening

In 2000, the European MH group^[33] formulated guidelines for RYR1 mutation screening with linkage data to other loci for some MH families, but the investigators emphasized the vital role for the IVCT in the diagnosis of MH. These guidelines have reduced the number of relatives requiring contracture testing without increasing risk^{[26] [34]} and include the following:

1. Confirmation of MHS in a family member (preferably a proband) by IVCT before genetic testing.
2. Use of 15 RYR1 mutations characterized by in vitro functional assays for the genetic protocol.
3. If a causative mutation is detected in a first-degree relative, MHS is confirmed, and IVCT is omitted.
4. If a familial mutation is not detected, IVCT is necessary.

Future Genetic Testing in North America

In contrast to European genetic efforts, only a small number of MH susceptible families have been extensively investigated by North American phenotyping, linkage analysis, and screening of specific genes. Collaborative protocols over the past 5 years between MH biopsy centers and molecular biologists have screened 140–160 unrelated MHS subjects for mutations in the RYR1 gene (see "Distribution of RYR1 Mutations"). In September 2002, MHAUS sponsored a meeting of molecular geneticists and MH experts to examine expanded screening in North America. They achieved consensus on several points:

1. Genetic testing limitations include low sensitivity due to diversity of the mutations and genes.
2. The RYR1 gene is the primary focus for genetic testing, but further studies are required for more complete understanding of the relationship between mutations and susceptibility.
3. Guidelines for referral and education are needed to establish clinical testing in a Clinical Laboratories Improvement Act (CLIA)-certified laboratory.
4. A North American MH RYR1 Mutation Panel was established and agreed on a table of mutations (see Table 29-1 ).