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

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Author(s)
Lee, Eric
Le, Trang
Zhu, Ying
Elakis, George
Turner, Anne
Lo, William
Venselaar, Hanka
Verrenkamp, Carol-Ann
Snow, Nicole
Mowat, David
Kirk, Edwin Philip
Sachdev, Rani
Smith, Janine
Brown, Natasha Jane
Wallis, Mathew
Barnett, Chris
McKenzie, Fiona
Freckmann, Mary-Louise
Collins, Felicity
Chopra, Maya
Gregersen, Nerine
Hayes, Ian
Rajagopalan, Sulekha
Tan, Tiong Yang
Stark, Zornitza
Savarirayan, Ravi
Yeung, Alison
Ades, Lesley
Gattas, Michael
Gibson, Kate
Gabbett, Michael
Amor, David John
Lattanzi, Wanda
Boyd, Simeon
Haan, Eric
Gianoutsos, Mark
Cox, Timothy Chilton
Buckley, Michael Francis
Roscioli, Tony
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2018
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Abstract

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.

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Genetics in Medicine

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20

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9

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Genetics

Clinical sciences

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