EP.129A probable new pathogenic variant in RYR1 gene? - 3 case reports

Abstract

Congenital myopathies represent a group of diseases ascribed as pathogenic variants in over 20 genes. Of these, disorders related to RYR1 gene are the most frequent, identified in 90% of central core disease patients; however, several histological phenotypes including findings with no specific features have been described. We report here 3 relatives from the same pedigree segregating a variant in RYR1 gene. A 39-year-old female manifested with distal upper limb weakness which progressed to involve the distal lower limb, proximal upper limb, as well as the face. The symptoms presenting with childhood onset had a slow progression. Creatine kinase(CK) was normal with EMG findings supporting a myopathy. Spirometry showed a restrictive respiratory disturbance. Muscle biopsy showed no specific findings except a type 1 predominance. Her son, 6 years-old, has proximal muscle weakness and facial weakness. CK normal. His brother, 45 years-old, has the same symptom. CK normal. Spirometry showed a restrictive respiratory disturbance. A muscle biopsy was performed showing no specific findings. Her father had the same symptoms with onset during childhood. Clinical exome sequencing revealed a heterozygous probably pathogenic variant in RYR1 gene: c.12083C>T (p. Ser4028Leu). This variant was found in the literature in 2 cases. The first was a boy, 6 years-old with onset disease at 2 years old. Muscle biopsy showed no specific findings however. The autosomal dominant or de novo cases are considered less severe. The ClinVar database classifies this variant as uncertain significance (VUS), although Invitae database has already reported a family with 3 members affected who segregated the same variant (data not published) Considering the similarities between our family and the missense variants previously reported as pathogenic we support that this variant is better classified as probable pathogenic.