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Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses
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Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses
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Journal Article
Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses
2020
Overview
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.
