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.