Pathogenic RYR1 variants more common in Asians

A recent Singapore study has found that pathogenic variants of the RYR1 gene tend to be more common in Asians, particularly in those of Indian descent. These variants are associated with conditions such as malignant hyperthermia (MH), central core disease, congenital fibre-type disproportion, and multiminicore disease.

“This paper also confirms that the variants found in our population are indeed rare and unique to individuals, suggesting a need to conduct genetic screening using sequencing rather than methods which look at specific mutations known to the database,” the researchers said.

Data were drawn from the SG10K pilot project, and variant pathogenicity was determined through the ClinVar and InterVar tools. Allele frequencies were compared among the major Singapore ethnic groups: Chinese, Indians, and Malays.

Subsequently, local allele frequencies were compared with that in populations in Europe, America, and across Asia using the ExAC, GenomAD, and GenomeAsia 100k databases.

All local RYR1 mutations occurred in exonic regions, and most were missense mutations or synonymous variants. ClinVar and InterVar found four pathogenic variants and two to six mutations that were likely pathogenic. All but two of these pathogenic/likely pathogenic variants were in mutational hotspots. [Sci Rep 2022;12:5429]

In terms of variant frequency, the researchers found six carriers of such pathogenic/likely pathogenic RYR1 variants out of a total of 4,810 individuals, yielding an overall allele frequency of 0.06 percent. People of Indian ethnicity made up half of the carriers (50 percent; p=0.009).

Notably, closer inspection of the variants’ ethnic distribution revealed that each RYR1 variant occurred exclusively in a single ethnicity. Of the four pathogenic variants, one was found only in Chinese individuals, two in Indians, and one in Malays.

Comparing across international populations further showed that two pathogenic and three likely pathogenic variants occurred at significantly greater allele frequencies in the Singaporean sample. In addition, one pathogenic and one likely pathogenic variant was more common among South Asians.

“In sum, allele frequencies of the pathogenic and likely pathogenic variants found in our study were generally higher amongst Asians (Singapore population and South Asian population) than globally,” the researchers said, noting that comparisons between Singapore and South Asia were inconclusive due to the variance in data reporting. “Data from other parts of Asia are also lacking.”  

“Currently there is no active screening for MH-susceptibility in Singapore due to the fact that MH is a rare condition and that genetic testing is still relatively costly to the individual. Screening for MH is only done through history-taking,” the researchers said.

“By understanding the variants in our population, it will be valuable in understanding the clinical utility of using these variants in the blood as a screening and diagnostic tool,” they added.