Novel Col12A1 variant expands the clinical picture of congenital myopathies with extracellular matrix defects

Abstract

Introduction: Mutations in the COL12A1 (collagen, type XII, alpha 1) gene have been described in a milder Bethlem‐like myopathy in 6 patients from 3 families (dominant missense), and in a severe congenital form with failure to attain ambulation in 2 patients in a single pedigree (recessive loss‐of‐function). Methods: We describe an 8‐year‐old girl of Polish origin who presented with profound hypotonia and joint hyperlaxity at birth after a pregnancy complicated by oligohydramnios and intrauterine growth retardation. Results: We identified a novel, potentially pathogenic heterozygous missense COL12A1 c.8329G>C (p.Gly2777Arg) variant using a targeted sequencing panel. Patient fibroblast studies confirmed intracellular retention of the COL12A1 protein, consistent with a dominant‐negative mutation. Conclusions: As our patient showed a more intermediate phenotype, this case expands the phenotypic spectrum for COL12A1 disorders. So far, COL12A1 disorders seem to cover much of the severity range of an Ehlers‐Danlos/Bethlem‐like myopathy overlap syndrome associated with both connective tissue abnormalities and muscle weakness. Muscle Nerve 55: 277–281, 2017