Transcript analysis for variant classification resolution in a child with primary ciliary dyskinesia

Alexander Ing, Alissa Wlodaver, Dawn Kirschmann, Erica Toledo, Christopher McCabe, Sabah Kadri, Mary Kate McIntyre, Joanne Salazar, Kristina Firestein, Joel Charrow, Victoria Sanders, Theresa Laguna, Kai Lee Yap*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Transcriptional analysis can be utilized to reconcile variants of uncertain significance, particularly those predicted to impact splicing. Laboratory analysis of the predicted mRNA transcript may allow inference of the in vivo impact of the variant and aid prediction of its clinical significance. We present a patient with classical features of primary ciliary dyskinesia (PCD) who was identified to have compound heterozygous variants in the DNAH11 gene (c.10691 + 2T> C, c.13523_13543dup21) via trio whole-exome sequencing in 2013. These variants were originally classified as Mutation and Likely Mutation. However, these variants were downgraded to variants of uncertain significance (VUSs) during reanalysis in 2016 because of uncertainty that they caused a loss of function of the gene. c.10691 + 2T >C is predicted to abrogate the canonical splice site and lead to the skipping of exon 65, but the adjoining of exon 64 and exon 66 in the DNAH11 transcript preserves the reading frame of the resultant protein. c.13523_13543dup21 is located in the last exon of the DNAH11 coding sequence, upstream of the canonical stop codon, which suggests a reduced likelihood to trigger nonsense-mediated decay (NMD). Transcriptional analysis was performed to characterize the impact of the variants, resulting in reclassification of c.10691+2T >C to Likely Pathogenic by providing evidence that it results in a deleterious effect and subsequent downstream reclassification of c.13523_13543dup21 to Likely Pathogenic as well. Our case illustrates the potential impact of transcriptional analysis on variant resolution, supporting its usage on variants that exert an unpredictable effect on splicing.

Original languageEnglish (US)
Article numbera005363
JournalCold Spring Harbor Molecular Case Studies
Issue number1
StatePublished - Feb 2021

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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