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    Diagnostic value of exome and whole genome sequencing in craniosynostosis.

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    Author
    Miller, KA; Twigg, SRF; McGowan, SJ; Phipps, JM; Fenwick, AL; Johnson, D; Wall, SA; Noons, P; Rees, KEM; Tidey, EA; ...
    Date
    2017-04
    Source Title
    Journal of Medical Genetics
    Publisher
    BMJ
    University of Melbourne Author/s
    Miller, Kerry
    Affiliation
    Paediatrics (RCH)
    Metadata
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    Document Type
    Journal Article
    Citations
    Miller, K. A., Twigg, S. R. F., McGowan, S. J., Phipps, J. M., Fenwick, A. L., Johnson, D., Wall, S. A., Noons, P., Rees, K. E. M., Tidey, E. A., Craft, J., Taylor, J., Taylor, J. C., Goos, J. A. C., Swagemakers, S. M. A., Mathijssen, I. M. J., van der Spek, P. J., Lord, H., Lester, T. ,... Wilkie, A. O. M. (2017). Diagnostic value of exome and whole genome sequencing in craniosynostosis.. J Med Genet, 54 (4), pp.260-268. https://doi.org/10.1136/jmedgenet-2016-104215.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/255403
    DOI
    10.1136/jmedgenet-2016-104215
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366069
    Abstract
    BACKGROUND: Craniosynostosis, the premature fusion of one or more cranial sutures, occurs in ∼1 in 2250 births, either in isolation or as part of a syndrome. Mutations in at least 57 genes have been associated with craniosynostosis, but only a minority of these are included in routine laboratory genetic testing. METHODS: We used exome or whole genome sequencing to seek a genetic cause in a cohort of 40 subjects with craniosynostosis, selected by clinical or molecular geneticists as being high-priority cases, and in whom prior clinically driven genetic testing had been negative. RESULTS: We identified likely associated mutations in 15 patients (37.5%), involving 14 different genes. All genes were mutated in single families, except for IL11RA (two families). We classified the other positive diagnoses as follows: commonly mutated craniosynostosis genes with atypical presentation (EFNB1, TWIST1); other core craniosynostosis genes (CDC45, MSX2, ZIC1); genes for which mutations are only rarely associated with craniosynostosis (FBN1, HUWE1, KRAS, STAT3); and known disease genes for which a causal relationship with craniosynostosis is currently unknown (AHDC1, NTRK2). In two further families, likely novel disease genes are currently undergoing functional validation. In 5 of the 15 positive cases, the (previously unanticipated) molecular diagnosis had immediate, actionable consequences for either genetic or medical management (mutations in EFNB1, FBN1, KRAS, NTRK2, STAT3). CONCLUSIONS: This substantial genetic heterogeneity, and the multiple actionable mutations identified, emphasises the benefits of exome/whole genome sequencing to identify causal mutations in craniosynostosis cases for which routine clinical testing has yielded negative results.

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