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