Saethre-Chotzen syndrome is an autosomal dominant disorder whose principal features are craniosynostosis primarily involving the coronal sutures and limb abnormalities including brachydactyly, broad great toes, and cutaneous syndactyly. Saethre-Chotzen syndrome is caused by mutations in the TWIST gene which maps to the chromosome 7p21-p22 region. The TWIST gene encodes a basic helix-loop-helix transcription factor which is activated by either homo- or heterodimerization and then binds to and regulates the transcription of a target gene(s). TWIST is important in murine embryonic development where it is expressed in mesodermally-derived tissues, especially of the craniofacial region and limb buds. Twenty-eight (16 published and 9 unpublished from our laboratory) different TWIST mutations including eight nonsense mutations throughout the coding region have been identified to date. A few Saethre-Chotzen cases of chromosomal deletions or translocation located within approximately 100 kb of the 3' coding region of TWIST are presumed to be due to loss of cis-regulatory sequences or position effects. Therefore, it has been presumed that these mutations result in loss of function or haploinsufficiency. We report here a sporadic case of Saethre-Chotzen syndrome with a new TWIST mutation. The patient was affected with brachycephaly, lateclosing and large fontanels, lowset frontal hairline, asymmetry of the face, severely hypoplastic maxillae, ptosis of the eyelids, hypertelorism, dacryostenosis, downslanting palpebral fissures, radioulnar synostosis, clinodactyly, broad great toes, hallux valgus, and cutaneous syndactyly of 2nd to 4th digits. Mutational analysis was performed by PCR amplification of the portion of the gene that encodes the helix-loop-helix region and direct sequencing. The mutation is a missense mutation, 445C->T (over 50 control samples did not have this change). This transition changes leucine 149 to a phenylalanine in the loop domain which is 100% conserved in humans and mice. Presumably for a missense mutation, the transcript level of the mutant and normal TWIST alleles would be the same. This mutation may alter the ability of TWIST to dimerize and consequently to bind its DNA target. When the protein(s) that dimerizes with TWIST and their DNA target(s) are identified, functional studies will be performed to determine the effect of this mutation.