The role of DLX5/6 regulatory elements in craniofacial development and craniosynostosis

Project Details


Premature closure of cranial vault sutures can lead to craniosynostosis (CS), which occurs in ~1 of 1,400 live births. Craniosynostosis is characterized by intracranial pressure, which can lead to blindness, deafness, seizures, and developmental disabilities. By genome-wide association analysis of a craniosynostosis patient cohort, we found a novel non-coding region at chromosome 7q21.3 (DLX5/6 locus), to be associated with coronal craniosynostosis. Interestingly, mutations in the DLX5/6 protein-coding sequences as well as non-coding regulatory sequences are linked to split-hand/foot malformation-1, a syndrome that is also characterized by craniofacial malformations, but the role of DLX5/6 in craniosynostosis was not investigated. Here, we will elucidate the regulatory elements of DLX5/6 that drive its expression during craniofacial development and cranial vault suture formation and will determine their role in craniosynostosis. Using epigenetic data and in vivo assay, we will characterize tissue-specific DLX5/6 enhancers. Next, we will analyze existing whole-genome sequencing data of craniosynostosis patients for rare variants within the DLX5/6 regulatory elements. Finally, we will study the in vivo effect of variants on DLX5/6 regulatory elements during craniofacial development. Taken together, this proposed study will open new venues towards understanding the genetic regulation of craniofacial development, craniosynostosis, and risk stratification.

Effective start/end date1/01/21 → …


  • United States-Israel Binational Science Foundation (BSF)


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