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Craniofacial abnormalities account for about one-third of all human congenital defects, but our understanding of the genetic mechanisms governing craniofacial development is incomplete. We show that GTF2IRD1 is a genetic determinant of mammalian craniofacial and cognitive development, and we implicate another member of the TFII-I transcription factor family, GTF2I, in both aspects. Gtf2ird1-null mice exhibit phenotypic abnormalities reminiscent of the human microdeletion disorder Williams-Beuren syndrome (WBS); craniofacial imaging reveals abnormalities in both skull and jaws that may arise through misregulation of goosecoid, a downstream target of Gtf2ird1. In humans, a rare WBS individual with an atypical deletion, including GTF2IRD1, shows facial dysmorphism and cognitive deficits that differ from those of classic WBS cases. We propose a mechanism of cumulative dosage effects of duplicated and diverged genes applicable to other human chromosomal disorders.

Original publication




Journal article



Publication Date





1184 - 1187


Adolescent, Adult, Animals, Cell Line, Child, Child, Preschool, Chromosomes, Human, Pair 7, Craniofacial Abnormalities, Face, Female, Gene Deletion, Goosecoid Protein, Homozygote, Humans, Infant, Infant, Newborn, Male, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Transgenic, Muscle Proteins, Nuclear Proteins, Skull, Trans-Activators, Transcription Factors, TFII, Williams Syndrome