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

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

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 an...

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Bibliographic Details
Published in:Clinical genetics Vol. 85; no. 4; pp. 359 - 364
Main Authors: Davis, E.E., Savage, J.H., Willer, J.R., Jiang, Y.-H., Angrist, M., Androutsopoulos, A., Katsanis, N.
Format: Journal Article
Language:English
Published: Oxford, UK Blackwell Publishing Ltd 01-04-2014
Subjects:
Adult
bioinformatic filtering
exome sequencing
Exons
Female
functional assays
Genes
Humans
Infant, Newborn
Introns
Male
Males
Membrane Transport Proteins - genetics
Membrane Transport Proteins - metabolism
Musculoskeletal diseases
Mutation
Osteochondrodysplasias - genetics
Pedigree
skeletal dysplasia
Transcription Factors - genetics
Transcription Factors - metabolism
Turkey
functional assays
exome sequencing
bioinformatic filtering
skeletal dysplasia
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Summary: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.
Bibliography:istex:384C62562E18BACD231D011FDA497E6D91A42B9D
ArticleID:CGE12189
Table S1. Genes on the X chromosome associated with skeletal system development (GO: 0001501).Table S2. Candidate variants identified through analysis of three exomes in pedigree DM040. The causal TRAPPC2 variant is highlighted in green.Table S3. Primer sequences used for Sanger confirmation and RT-PCR of TRAPPC2.Table S4. Whole-exome capture and Illumina sequencing coverage statistics for DM040.
ark:/67375/WNG-RCMNPLZC-X
None to declare.
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0009-9163
1399-0004
DOI:10.1111/cge.12189