Genetics of Nonsyndromic Craniosynostosis

Summary: Occurring once in every 2000 live births, craniosynostosis is one of the most frequent congenital anomalies encountered by the craniofacial surgeon. Syndromic craniosynostoses account for approximately 15 percent of cases and demonstrate Mendelian patterns of inheritance with well-established genetic causes; however, nonsyndromic craniosynostoses, which account for approximately 85 percent of cases, are genetically heterogeneous and largely unexplored. Nonsyndromic craniosynostosis is sporadic in more than 95 percent of affected families; thus, surgeons have suggested for decades that nonsyndromic craniosynostosis is likely a fluke occurrence. Contrary to this, recent studies have established that genetics underlie a substantial fraction of nonsyndromic craniosynostosis risk. Given the predominantly sporadic occurrence of disease, parents are often bewildered by the primary occurrence of nonsyndromic craniosynostosis 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 and the future offspring of the affected child. The diagnostic utility of existing panels for nonsyndromic craniosynostosis, however, is extremely low, and these tests are quite costly. Recent genetic studies have identified several novel genes and pathways that cause nonsyndromic craniosynostosis, providing genetic evidence linking the causes of syndromic and nonsyndromic craniosynostoses, and allowing for genotype-based prediction of risk of recurrence in some nonsyndromic families. Based on analysis of exome sequence data from 384 families, the authors provide recommendations for a new genetic testing protocol for children with nonsyndromic craniosynostosis, which include testing nonsyndromic cases of sagittal, metopic, and coronal craniosynostosis.