Genetics of non-syndromic craniosynostosis

SUMMARY: Occurring once in every 2,000 live births, craniosynostosis is one of the most frequent congenital anomalies encountered by the craniofacial surgeon. Syndromic craniosynostoses account for ~15% of cases and demonstrate Mendelian patterns of inheritance with well-established genetic etiologies1,2, however non-syndromic craniosynostoses (NSC), which account for ~85% of cases2, are genetically heterogeneous and largely unexplored. NSC is sporadic in >95% of affected families3, thus surgeons have suggested for decades that NSC is likely a fluke occurrence. Contrary to this, recent studies have established that genetics underlie a substantial fraction of NSC risk. Given the predominantly sporadic occurrence of disease, parents are often bewildered by the primary occurrence of NSC or even recurrence in their own families and request genetic testing. Existing genetic testing panels are useful when the phenotype strongly resembles a known syndrome, wherein the risk of disease recurrence can be accurately predicted for future offspring of the parents as well as the future offspring of the affected child. The diagnostic utility of existing panels for NSC, however, is extremely low, while these tests are quite costly. Recent genetic studies have identified several novel genes and pathways that cause NSC, providing genetic evidence linking the pathoetiology of syndromic and non-syndromic craniosynostoses, and allowing for genotype-based prediction of risk of recurrence in some non-syndromic families. Based on analysis of exome sequence data from 384 families, we provide recommendations for a new genetic testing protocol for children with NSC, which include testing non-syndromic cases of sagittal, metopic, and coronal craniosynostosis. Financial Disclosure Statement: No authors have any disclosures. Presented at: N/A Correspondence should be addressed to: Andrew T. Timberlake PhD, John A. Persing MD, Section of Plastic and Reconstructive Surgery, Yale School of Medicine, 330 Cedar Street, 3rd Floor Boardman Building, New Haven, CT 06520, Andrew.timberlake@yale.edu, John.persing@yale.edu ©2018American Society of Plastic Surgeons