Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT

Erica Ellen Davis, J. H. Savage, J. R. Willer, Y. H. Jiang, M. Angrist, A. Androutsopoulos, Elias Nicholas Katsanis*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Skeletal dysplasias are challenging to diagnose because of their phenotypic variability, genetic heterogeneity, and diverse inheritance patterns. We conducted whole exome sequencing of a Turkish male with a suspected X-linked skeletal dysplasia of unknown etiology as well as his unaffected mother and maternal uncle. Bioinformatic filtering of variants implicated in skeletal system development revealed a novel hemizygous mutation, c.341-(11_9)delAAT, in an intron of TRAPPC2, the causative locus of spondyloepiphyseal dysplasia tarda (SEDT). We show that this deletion leads to the loss of wild-type TRAPPC2 and the generation of two functionally impaired mRNAs in patient cells. These consequences are predicted to disrupt function of SEDLIN/TRAPPC2. The clinical and research data were returned, with appropriate caveats, to the patient and informed his disease status and reproductive choices. Our findings expand the allelic repertoire of SEDT and show how prior filtering of the morbid human genome informed by inheritance pattern and phenotype, when combined with appropriate functional tests in patient-derived cells, can expedite discovery, overcome issues of missing data and help interpret variants of unknown significance. Finally, this example shows how the return of a clinically confirmed mutational finding, supported by research allele pathogenicity data, can assist individuals with inherited disorders with life choices.

Original languageEnglish (US)
Pages (from-to)359-364
Number of pages6
JournalClinical genetics
Issue number4
StatePublished - Apr 2014


  • Bioinformatic filtering
  • Exome sequencing
  • Functional assays
  • Skeletal dysplasia

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics


Dive into the research topics of 'Whole exome sequencing and functional studies identify an intronic mutation in TRAPPC2 that causes SEDT'. Together they form a unique fingerprint.

Cite this