Correlation of phenotype and genotype in Croatian patients with Collagen VI (COL6) gene de novo mutations

Abstract

Muscle dystrophies present very heterogenous group of muscle disorders. Objective: To present variability of phenotype in Croatian patients with collagen VI gene mutations and diagnostic significance of muscle MR imaging. Methods: Electromyography (EMG), muscle biopsy, cardiac ultrasound, whole exome sequencing (WES) and muscle MR imaging (MRI) were performed in all patients. Results: We present 6 patients from 3 families: 5 children at the age 6–14 years and 1 adult (mother of one of the patients). Clinical features of muscle weakness primarily of the limb girdle type, positive Gowers sign, and elbow, hip and finger contractures were present at the age 14 months–4 years. CK levels were normal or mildly elevated (up to 400 U/L), EMG revealed myopathic pattern. Muscle biopsy performed in 4 children revealed muscle fibers variability and increased connective tissue, while in 2 children signs of neurogenic atrophy were present as well. Whole exome sequencing (WES) confirmed COL6 mutations in all 6 patients and their parents. Diagnosis was supported by muscle MRI of the lower limbs. Two patients (mother and daughter) developed severe type of disease and wheelchair dependency at the age 40 and 15 years. Cardiac ultrasound revealed borderline cardyomyopathy in one male patient at the age of 14 years. Conclusion: COL6-related myopathy is important in differential diagnosis of patients with muscle weakness and hypotrophy of limb girdle phenotype and congenital myopathies with normal or mildly elevated CK values. They can be inherited in both recessive and dominant traits. Phenotype and muscle biopsy are often not informative or specific. Muscle MR imaging, along with WES is important in diagnosis of COL6-related myopathies, including cases with atypical clinical phenotype or in de novo COL6 gene mutations.