Rare Duplication in the RYR1 Gene Causing Malignant Hyperthermia and Clinical Variability

Area of Science:

• Genetics
• Molecular Biology
• Clinical Medicine

Background:

• RYR1 gene variants are primarily linked to Malignant Hyperthermia susceptibility.
• While missense variants are common, insertions and duplications constitute less than 10% of RYR1 variants.
• The phenotypic variability of Malignant Hyperthermia necessitates investigating rare RYR1 variants.

Purpose of the Study:

• To investigate the impact of a rare RYR1 gene duplication on Malignant Hyperthermia susceptibility.
• To reclassify a Variant of Uncertain Significance (VUS) using molecular and physiological data.
• To explore the pathomechanisms underlying RYR1 duplication variants.

Main Methods:

• Exome variant screening to identify genetic variants.
• In vitro contracture testing to assess muscle function.
• Muscle biopsy analysis including anatomopathology and RT-qPCR for RYR1 expression.

Main Results:

• A family identified with two siblings carrying an 18-base pair duplication in RYR1 exon 91 (c.12835_12852 dupGAGGGCGCGGCGGGGCTC:162 p.G4279_T4284insAAGLEG).
• The variant, rare in gnomAD (0.0007%) and absent in controls, was reclassified from VUS to borderline likely pathogenic.
• Patients exhibited approximately 50% reduced RYR1 mRNA expression, indicating a potential hypomorphic allele.

Conclusions:

• This study supports that RYR1 duplications can lead to structural defects and a more severe Malignant Hyperthermia phenotype.
• Unlike typical gain-of-function mechanisms, small RYR1 insertions/duplications may cause loss of function or protein misfolding.
• The findings contribute to understanding the diverse pathomechanisms of RYR1 variants in Malignant Hyperthermia.