A craniosynostosis massively parallel sequencing panel study in 309 Australian and New Zealand patients: findings and recommendations

Eric Lee, Trang Le, Ying Zhu, George Elakis, Anne Turner, William Lo, Hanka Venselaar, Carol-Ann Verrenkamp, Nicole Snow, David Mowat, Edwin Philip Kirk, Rani Sachdev, Janine Smith, Natasha Jane Brown, Mathew Wallis, Chris Barnett, Fiona Mckenzie, Mary-Louise Freckmann, Felicity Collins, Maya ChopraNerine Gregersen, Ian Hayes, Sulekha Rajagopalan, Tiong Yang Tan, Zornitza Stark, Ravi Savarirayan, Alison Yeung, Lesley Adès, Michael Gattas, Kate Gibson, Michael Gabbett, David John Amor, Wanda Lattanzi, Simeon Boyd, Eric Haan, Mark Gianoutsos, Timothy Chilton Cox, Michael Francis Buckley, Tony Roscioli

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

22 Citazioni (Scopus)


Purpose: The craniosynostoses are characterized by premature fusion of one or more cranial sutures. The relative contribution of previously reported genes to craniosynostosis in large cohorts is unclear. Here we report on the use of a massively parallel sequencing panel in individuals with craniosynostosis without a prior molecular diagnosis. Methods: A 20-gene panel was designed based on the genes’ association with craniosynostosis, and clinically validated through retrospective testing of an Australian and New Zealand cohort of 233 individuals with craniosynostosis in whom previous testing had not identified a causative variant within FGFR1-3 hot-spot regions or the TWIST1 gene. An additional 76 individuals were tested prospectively. Results: Pathogenic or likely pathogenic variants in non-FGFR genes were identified in 43 individuals, with diagnostic yields of 14% and 15% in retrospective and prospective cohorts, respectively. Variants were identified most frequently in TCF12 (N = 22) and EFNB1 (N = 8), typically in individuals with nonsyndromic coronal craniosynostosis or TWIST1-negative clinically suspected Saethre–Chotzen syndrome. Clinically significant variants were also identified in ALX4, EFNA4, ERF, and FGF10. Conclusion: These findings support the clinical utility of a massively parallel sequencing panel for craniosynostosis. TCF12 and EFNB1 should be included in genetic testing for nonsyndromic coronal craniosynostosis or clinically suspected Saethre–Chotzen syndrome.
Lingua originaleEnglish
pagine (da-a)1061-1068
Numero di pagine8
RivistaGenetics in Medicine
Stato di pubblicazionePubblicato - 2018


  • Australia
  • Basic Helix-Loop-Helix Transcription Factors
  • Cohort Studies
  • Cranial Sutures
  • Craniosynostoses
  • DNA-Binding Proteins
  • EFNB1
  • Ephrin-B1
  • Female
  • Fibroblast Growth Factor 10
  • Genetic Testing
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • New Zealand
  • Nuclear Proteins
  • Prospective Studies
  • Receptor, Fibroblast Growth Factor, Type 1
  • Repressor Proteins
  • Retrospective Studies
  • TCF12
  • Transcription Factors
  • Twist-Related Protein 1
  • coronal
  • craniosynostosis
  • panel


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