De novo RYR1 variant c.7108_7109delinsAAGCC (p.Gly2370delinsLysPro) causes life-threatening malignant hyperthermia: reclassification from VUS to pathogenic

Abstract

Malignant hyperthermia (MH) is a rare, life-threatening pharmacogenetic disorder primarily associated with variants in the RYR1 gene. A significant proportion of identified RYR1 variants are classified as Variants of Uncertain Significance (VUS), posing a major challenge for clinical management and genetic counseling. We report a case of a 53-year-old male (proband) who developed fulminant MH during general anesthesia. Following clinical stabilization, whole-exome sequencing (WES) was performed. The initial analysis reported several variants of uncertain significance (VUS). Based on the compelling MH phenotype, the RYR1 gene was prioritized for further investigation. The candidate variant was validated by Sanger sequencing in the proband and his unaffected son and sister. WES revealed a heterozygous RYR1 variant, c.7108_7109delinsAAGCC (p.Gly2370delinsLysPro), initially classified as a VUS. Crucially, Sanger sequencing confirmed that this variant was absent in his unaffected son and sister, providing strong indirect evidence for a de novo origin. The proband’s clinical presentation was classic for MH: hyperthermia (39 °C), tachycardia, hypercapnia, muscle rigidity, hyperkalemia, and markedly elevated creatine kinase/myoglobin, which responded to dantrolene. Re-evaluation using ACMG/AMP guidelines identified the following key pathogenic evidence: PS4 (specific MH phenotype), supporting PS2 (probable de novo), PM2 (absent in population databases), PM4(in-frame indel), PP1(co-segregation in a micro-family), PP2( RYR1 is a known MH gene), PP3(computational evidence of deleteriousness), and PP4 (highly specific phenotype). This study is the first to report and validate the pathogenicity of the RYR1 c.7108_7109delinsAAGCC variant. By integrating a definitive clinical MH episode with familial segregation data, we successfully reclassified this VUS as Pathogenic. Our findings underscore the critical importance of phenotype-driven reassessment of VUS using the ACMG framework and provide definitive guidance for the lifelong anesthetic management of the proband and his family.