Key result
Compound heterozygous RYR1 variants linked to severe congenital myopathy with normal CK levels.
Why the study?
Genotype-phenotype correlations in RYR1-related myopathy are complicated due to the large size of the gene and heterogeneous phenotypes.
Case Report (n=7)
Whole genome sequencing can identify deep intronic splice variants in RYR1, aiding in genotype-phenotype correlations for severe congenital myopathies.
Hypothesis-generating for deep intronic RYR1 variants in congenital myopathy; leaves open need for functional validation before diagnostic adoption.
Pathogenic variants in the ryanodine receptor 1 (RYR1) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype–phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient’s phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype–phenotype correlations.
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Janßen et al. (2024) conducted a case report in Severe congenital myopathy (n=7). Compound heterozygous RYR1 variants was evaluated on Clinical phenotype and disease severity. Compound heterozygous RYR1 variants, including a deep intronic splice variant, were associated with severe congenital myopathy characterized by congenital onset, muscular hypotonia, and normal CK levels.
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