Mutation Screening of Candidate Genes in Patients with Nonsyndromic Sagittal Craniosynostosis
Published Date:Mar 2016
Source:Plast Reconstr Surg. 137(3):952-961.
Genetic Association Studies
Genetic Predisposition To Disease
Molecular Sequence Data
Receptor, Fibroblast Growth Factor, Type 1
Sensitivity And Specificity
Twist-Related Protein 1
Pubmed Central ID:PMC4770826
Funding:R01 DE022988/DE/NIDCR NIH HHS/United States
1 P01 HD078233/HD/NICHD NIH HHS/United States
5 R01DD000350/DD/NCBDD CDC HHS/United States
R01 DD000350/DD/NCBDD CDC HHS/United States
P01 HD078233/HD/NICHD NIH HHS/United States
Craniosynostosis is a condition that includes the premature fusion of one or multiple cranial sutures. Among various craniosynostosis forms, midline sagittal nonsyndromic craniosynostosis (sNSC) is the most prevalent. Although different gene mutations have been identified in some craniosynostosis syndromes, the etiology of sNSC remains largely unknown.
To screen for candidate genes for sNSC, we performed Sanger sequencing on DNA from 93 sNSC patients from a population-based, case-control study conducted in Iowa and New York states. FGFR1-3 mutational hotspots known to be associated with sNSC, and the entire TWIST1, RAB23, BMP2 coding regions were screened because of their known roles in human nonsyndromic or syndromic sagittal craniosynostosis, expression patterns, and/or animal model studies.
We identified two rare variants in our cohort. An insertion c.730_731insG in FGFR1, which led to a premature stop codon, was predicted to abolish the entire IgIII 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 to have 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 .000831 percent in ExAC database.
The low mutation detection rate indicates that these genes only account for a very small proportion of sNSC patients. Our results add to the perception that sNSC is a complex developmental defect with considerable genetic heterogeneity.
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