NIH Research Festival
Purpose: Exome and genome sequencing are increasingly used in healthcare and research to identify genetic variations. ACMG recommendations for returning pathogenic variants as secondary findings include RYR1. The aim of this study is to assess RYR1 variants from various mutation databases for pathogenicity to Malignant Hyperthermia Susceptibility (MHS) – a serious, life-threatening disorder triggered by certain anesthetics - to support the identification of individuals who may have MHS found incidentally by sequencing. Methods: We adapted ACMG methodology to MHS for reassessing RYR1 variants as an early stage in developing variant interpretation guidelines specific to the disorder and to aid the evaluation of secondary findings. Results: A combined list of over 600 RYR1 variants were reduced, using an algorithm that filtered results based on frequency and quality metrics, then scored on a five-point pathogenicity scale using ACMG criteria. Among the 289 variants analyzed, 126 were designated as pathogenic or likely pathogenic, and 163 were in the unknown significance to benign category. Conclusions: Revised variant guidelines for interpretation of sequence variants expands the number of MHS variants that can be returned as incidental findings and used for pharmacogenetics. Clinical genomics can be used to find more efficient methods of determining the ability of a variant to cause disease. The widespread implementation of genomic screening, coupled with the assessment of known RYR1 variants, could lead to a dramatic reduction in morbidity and mortality from MHS. The work is a critical initial effort toward genomic screening for MHS in the wider population.
Scientific Focus Area: Genetics and Genomics
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