Stergachis*, Blue*, et al. (2023) Full-length isoform sequencing for resolving the molecular basis of Charcot-Marie-Tooth 2A. Neurology Genetics, 9, e200090. PMCID: PMC10409571.
*co-first authors
Although 90% of patients with Charcot-Marie-Tooth 2A (CMT2A) [MIM: 609260] have dominant-negative pathogenic variants in MFN2, recessive inheritance has been reported for patients with biallelic loss-of-function variants. We identified a patient with a homozygous intronic MFN2 c.600-31T>G variant within a large region of paternal uniparental isodisomy. The combination of short-read and full-length transcriptomics revealed that this variant creates 5 distinct altered splicing transcripts subject to nonsense mediated decay. Functional assays confirm that this variant leads to MFN2 dysfunction and deficient MFN2 levels in patient cells. This study is important because it highlights how we can use full-length isoform sequencing to better understand the molecular mechanism of undiagnosed rare diseases in general, and expands our understanding of the pathogenesis of CMT2A.Contributing consortia:Undiagnosed Diseases Network, University of Washington Center for Mendelian Genomics