Diagnostic value of exome and whole genome sequencing in craniosynostosis.

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Miller, KA; Twigg, SRF; McGowan, SJ; Phipps, JM; Fenwick, AL; Johnson, D; Wall, SA; Noons, P; Rees, KEM; Tidey, EA; ...Date
2017-04Source Title
Journal of Medical GeneticsPublisher
BMJUniversity of Melbourne Author/s
Miller, KerryAffiliation
Paediatrics (RCH)Metadata
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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 AccessOpen Access at PMC
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366069Abstract
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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