BACKGROUND: Craniosynostosis is a condition that includes the premature fusion 
of one or multiple cranial sutures. Among various craniosynostosis forms, 
sagittal nonsyndromic craniosynostosis is the most prevalent. Although different 
gene mutations have been identified in some craniosynostosis syndromes, the 
cause of sagittal nonsyndromic craniosynostosis remains largely unknown.
METHODS: To screen for candidate genes for sagittal nonsyndromic 
craniosynostosis, the authors sequenced DNA of 93 sagittal nonsyndromic 
craniosynostosis patients from a population-based study conducted in Iowa and 
New York states. FGFR1-3 mutational hotspots and the entire TWIST1, RAB23, and 
BMP2 coding regions were screened because of their known roles in human 
nonsyndromic or syndromic sagittal craniosynostosis, expression patterns, and/or 
animal model studies.
RESULTS: The authors identified two rare variants in their cohort. A FGFR1 
insertion c.730_731insG, which led to a premature stop codon, was predicted to 
abolish the entire immunoglobulin-like III domain, including the ligand-binding 
region. A c.439C>G variant was observed in TWIST1 at its highly conserved loop 
domain in another patient. The patient's mother harbored the same variant and 
was reported with jaw abnormalities. These two variants were not detected in 116 
alleles from unaffected controls or seen in the several databases; however, 
TWIST1 variant was found in a low frequency of 0.000831 percent in Exome 
Aggregation Consortium database.
CONCLUSIONS: The low mutation detection rate indicates that these genes account 
for only a small proportion of sagittal nonsyndromic craniosynostosis patients. 
The authors' results add to the perception that sagittal nonsyndromic 
craniosynostosis is a complex developmental defect with considerable genetic 
heterogeneity.
CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.