Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses.

Journal Article (Journal Article)

PURPOSE: Guidelines by professional organizations for assessing variant pathogenicity include the recommendation to utilize biologically relevant transcripts; however, there is variability in transcript selection by laboratories. METHODS: We describe three patients whose genomic results were incorrect, because alternative transcripts and tissue expression patterns were not considered by the commercial laboratories. RESULTS: In individual 1, a pathogenic coding variant in a brain-expressed isoform of CKDL5 was missed twice on sequencing, because the variant was intronic in the transcripts considered in analysis. In individual 2, a microdeletion affecting KMT2C was not reported on microarray, since deletions of proximal exons in this gene are seen in healthy individuals; however, this individual had a more distal deletion involving the brain-expressed KMT2C isoform, giving her a diagnosis of Kleefstra syndrome. Individual 3 was reported to have a pathogenic variant in exon 10 of OFD1 on exome, but had no typical features of the OFD1-related disorders. Since exon 10 is spliced from the more biologically relevant transcripts of OFD1, it was determined that he did not have an OFD1 disorder. CONCLUSION: These examples illustrate the importance of considering alternative transcripts as a potential confounder when genetic results are negative or discordant with the phenotype.

Full Text

Duke Authors

Cited Authors

  • Schoch, K; Tan, QK-G; Stong, N; Deak, KL; McConkie-Rosell, A; McDonald, MT; Undiagnosed Diseases Network, ; Goldstein, DB; Jiang, Y-H; Shashi, V

Published Date

  • July 2020

Published In

Volume / Issue

  • 22 / 7

Start / End Page

  • 1269 - 1275

PubMed ID

  • 32366967

Pubmed Central ID

  • PMC7335342

Electronic International Standard Serial Number (EISSN)

  • 1530-0366

Digital Object Identifier (DOI)

  • 10.1038/s41436-020-0781-x


  • eng

Conference Location

  • United States