Genotype and clinical care correlations in craniosynostosis: Findings from a cohort of 630 Australian and New Zealand patients

Tony Roscioli, George Elakis, Cox Timothy, David Moon, Hanka Venselaar, Anne Turner, Trang Le, Emma Hackett, Eric Haan, Alison Colley, David Mowat, Lisa Worgan, Edwin Kirk, Rani Sachdev, Elizabeth Thompson, Michael Gabbett, Julie McGaughran, Kate Gibson, Michael Gattas, Mary-Louise FreckmannJoanne Dixon, Lies Hoefsloot, Michael Field, Anna Hackett, Benjamin Kamien, Matthew Edwards, Lesley Ades, Felicity Collins, Meredith Wilson, Ravi Savarirayan, Tiong Tan, David Amor, George McGillivray, Susan White, Ian Glass, David David, Peter Anderson, Mark Gianoutsos, Michael Buckley

    Research output: Contribution to journalArticlepeer-review

    38 Citations (Scopus)


    Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

    Original languageEnglish
    Pages (from-to)259-270
    Number of pages12
    Issue number4
    Publication statusPublished - Nov 2013


    • Apert
    • Crouzon
    • Fibroblast growth factor receptor
    • Muenke
    • Pfeiffer
    • Saethre-Chotzen
    • TWIST1


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