A disturbed interaction between TBX15 and ADAMTS2 during embryonic development may cause a previously undescribed craniofacial malformation disorder. Researchers have investigated nine patients presenting a unique soft palate malformation that is different from frequently occurring cleft palate. The patients had unilateral soft palate hypoplasia with a defective sphenoid bone in the pterygoid process but an intact uvula, and some of them showed additional dysmorphic features. Exome sequencing revealed de novo variants in TBX15 and ADAMTS2 as potentially causative genetic defects.

The Chinese study published in Human Mutation establishes for the first time a link between TBX15 and ADAMTS2 during embryonic palate development. Like other members of the T-box family, TBX15 encodes a transcription factor containing the characteristic DNA-binding domain T-box. Homozygous loss-of-function variants in TBX15 have previously been reported to cause Cousin syndrome, a skeletal malformation disorder. ADAMTS2 belongs to the family of ADAMTS genes, which code for metalloproteases that are involved in the cleavage of extracellular matrix molecules and in the processing of collagens. Inactivating ADAMTS2 variants cause a subtype of Ehlers-Danlos syndrome, a connective tissue disorder. Little has been know so far about the role of TBX15 and ADAMTS2 in soft palate development. The authors of the study conclude from their analyses that TBX15 and ADAMTS2 are colocalized during soft palate development and that TBX15 binds to the ADAMTS2 promoter region, thereby activating the signaling pathway.