G.P.22 Possible mutation dependent mechanisms for intra-familial variation of severity in Collagen VI-Related Myopathies (COL6-RM)

Abstract COL6-RM are a group of disorders with variable expressivity, from severe Ullrich congenital muscular dystrophy (UCMD) to the milder Bethlem myopathy (BM). The spectrum includes weakness, joint hyperlaxity, contractures, keratosis pilaris, keloid scarring, and respiratory insufficiency. Diagnosis is based on presentation, characteristic muscle imaging changes, and immunohistochemical findings in muscle and fibroblasts. Genetic confirmation is obtained through COL6A1–A3 sequencing. Mutations in COL6-RM can act via a dominant or recessive mechanism and may be inherited or de novo. Understanding the underlying genetic mechanism is essential for providing recurrence risk and genetic counseling. We report three families with novel mutations and pathogenic mechanisms predicted to cause variable severity of COL6-RM. A 40-yr-old male in Family 1 has typical findings of BM, while his 11-yr-old daughter has a UCMD phenotype. Fibroblasts showed reduced expression of Col6 in both. Genetic results were suggestive of somatic mosaicism in the father, whereas the child was a full carrier of a novel COL6A2 heterozygous c.900+1G>A mutation resulting in exon 7 skipping. In Family 2, two brothers presented with weakness, contractures, and keratosis pilaris. Their 43-yr-old father had only finger contractures but was found to have typical COL6 imaging findings on muscle ultrasound and MRI. Genetic testing revealed a variant in IVS9-22A>G in COL6A1 resulting in exon 10 skipping, segregating in all 3. Fibroblasts showed reduced expression of COL6. Family 3 showed three generations of AD inherited mutation c.6309+10C>G in COL6A3 creating a novel ‘leaking’ splice donor site. Phenotypic variability ranged from mild to severe contractures unrelated to muscle involvement. Advances in understanding of the genetics of Col6 myopathy will aid future clinical trials where modulation of the disease phenotype will serve as the target for intervention.