A Novel Deep Intronic Variant in LAMA2 Identified by RNA Sequencing

LAMA2-related muscular dystrophy is caused by pathogenic variants of the alpha2 subunit of Laminin. This common form of muscular dystrophy is characterized by elevated CK >1000IU/L, dystrophic changes on muscle biopsy, complete or partial absence of merosin staining, and both central and peripheral nervous system involvement [ [1] Sarkozy A Foley AR Zambon AA Bönnemann CG Muntoni F. LAMA2-Related Dystrophies: Clinical Phenotypes, Disease Biomarkers, and Clinical Trial Readiness. Front Mol Neurosci. 2020; 13 (Aug 5PMID: 32848593; PMCID: PMC7419697): 123https://doi.org/10.3389/fnmol.2020.00123 Crossref PubMed Scopus (44) Google Scholar ]. Advancements in genomic testing using NGS and wider application of RNA sequencing has expanded our knowledge of novel non-coding pathogenic variants in LAMA2. RNA sequencing is an increasingly utilized technique to directly analyze the transcriptome, through creation of a complementary DNA (cDNA) from the transcript within a tissue sample [ [2] Cummings BB Marshall JL Tukiainen T Lek M Donkervoort S Foley AR et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci Transl Med. 2017; 9 (Apr 19PMID: 28424332; PMCID: PMC5548421): eaal5209https://doi.org/10.1126/scitranslmed.aal5209 Crossref PubMed Scopus (453) Google Scholar ]. Here we describe a homozygous deep intronic variant that produces a novel splice junction in LAMA2 identified by RNA sequencing analysis in a patient with a clinical phenotype in keeping with LAMA2-related muscular dystrophy. Furthermore, in this case merosin staining was retained suggestive of a functional deficit.