485P Familial case of Bethlem myopathy caused by an ALU insertion in COL6A2

• Published in: Neuromuscular disorders : NMD 2024-10, Vol.43, p.104441, Article 104441.322
• Main Authors: Luce, L., Demidov, G., Duff, J., McFarlane, A., Segarra-Casas, A., Laurie, S., de Visser, M., van der Kooi, A., Straub, V., Töpf, A.
• Format: Article
• Language: English
• ISSN: 0960-8966
• DOI: 10.1016/j.nmd.2024.07.331

Ullrich congenital muscular dystrophy and Bethlem myopathy (BM) are a spectrum of diseases caused by molecular alterations in COL6A1, COL6A2, COL6A3 and COL12A1. BM is the milder end of the spectrum as patients present mild symptoms and remain ambulant till adulthood. Here, we present a familial case of BM, where the 5 affected members over two generations, presented onset of symptoms in childhood, slow progressive proximal muscle weakness of upper and lower limbs, joint contractures, and difficulty walking. The index case showed muscle MRI findings suggestive of collagenopathy. A DNA sample from the index case was initially analysed by whole exome sequencing (WES). No single nucleotide nor indel variants in the COL6 and COL12 genes were identified. Exome data was then analysed applying a pipeline for copy number and structural variants as part of the Solve-RD project. Candidate variants were segregated and further studied at the mRNA level. Re-analysis of WES data detected a large heterozygous insertion in exon 10 of COL6A2, and its exact size and complete sequence was determined by PCR-sanger sequencing. The variant consists of an insertion of ∼321bp between positions c.989_990 (hg19:chr21:47536717), 10bp before the 3’ end of exon 10. Two key elements of the inserted sequence indicate that it stems from an Alu element: a target site duplication and the conserved A5TACA6 motif. Segregation analysis demonstrated that the insertion co-segregates with the presence of clinical symptoms, while the non-affected members of the family included in this study did not carry the variant. RNA analysis of the index patient's fibroblasts showed the existence of an alternative transcript lacking exon 10, leading to an in-frame deletion. Here, we have confirmed the clinical diagnosis of BM by the insertion of an Alu element in COL6A2. To our knowledge, this constitutes the second case so far of collagenopathies caused by Alu elements, but the first mapping in the exonic region of the gene.