American Journal of Medical Genetics 110:136–143 (2002) Genetic Analysis of Patients With the Saethre-Chotzen Phenotype Kathy Chun, 1,2 Ahmad S. Teebi, 2,3 Jack H. Jung, 4 Shelley Kennedy, 2,3 Rachel Laframboise, 5 Wendy S. Meschino, 6 Kazuhiko Nakabayashi, 3 Stephen W. Scherer, 3 Peter N. Ray, 1,3 and Ikuko Teshima 1 * 1 Department of Pediatric Laboratory Medicine, Hospital for Sick Children and University of Toronto, Toronto, Canada 2 Department of Pediatrics, Division of Clinical Genetics, Hospital for Sick Children and University of Toronto, Toronto, Canada 3 Department of Genetics, Hospital for Sick Children and University of Toronto, Toronto, Canada 4 Division of Medical Genetics, Children’s Hospital of Western Ontario and University of Western Ontario, London, Canada 5 Departement Me´decine Ge´ne´tique, Centre deRecherche du Centre Hospitalier del’Universite´, Laval,Canada 6 Department of Genetics, North York General Hospital, Toronto, Canada Saethre-Chotzen syndrome is a common craniosynostosis syndrome characterized by craniofacial and limb anomalies. Intra- genic mutations of the TWIST gene within 7p21 have been identified as a cause of this disorder. There is phenotypic overlap with other craniosynostosis syndromes, and in- tragenic mutations in FGFR2 (fibroblast growth factor receptor 2) and FGFR3 (fibro- blast growth factor receptor 3) have been demonstrated in the other conditions. Furthermore, complete gene deletions of TWIST have also been found in a signific- ant proportion of patients with Saethre- Chotzen syndrome. We investigated 11 patients clinically identified as having the Saethre-Chotzen phenotype and 4 patients with craniosynostosis but without a clear diagnosis. Of the patients with the Saethre- Chotzen phenotype, four were found to carry the FGFR3 P250R mutation, three were found to be heterozygous for three different novel mutations in the coding region of TWIST, and two were found to have a deletion of one copy of the entire TWIST gene. Developmental delay was a distinguishing feature of the patients with deletions, compared to patients with intra- genic mutations of TWIST, in agreement with the results of Johnson et al. [1998: Am J Hum Genet 63:1282–1293]. No mutations were found for the four patients with craniosynostosis without a clear diagnosis. Therefore, 9 of our 11 patients (82%) with the Saethre-Chotzen phenotype had detectable genetic changes in FGFR3 or TWIST. We propose that initial screening for the FGFR3 P250R mutation, followed by sequencing of TWIST and then fluorescence in situ hybri- dization (FISH) for deletion detection of TWIST, is sufficient to detect mutations in > 80% of patients with the Saethre-Chotzen phenotype. ß 2002 Wiley-Liss, Inc. KEY WORDS: Saethre-Chotzen phenotype; craniosynostosis; TWIST; FGFR3; mutation; deletion INTRODUCTION Craniosynostosis is the premature fusion of one or more cranial sutures and occurs in 1 in 2,500 new- borns (reviewed by Wilkie [1997]). Saethre-Chotzen syndrome (acrocephalosyndactyly type III (ACS III); OMIM 101400) is one of the most common craniosy- nostosis syndromes and demonstrates autosomal domi- nant inheritance. This disorder is characterized by craniofacial and limb anomalies. Synostosis of coronal sutures, brachycephaly, hypertelorism, ptosis, facial asymmetry, deviated nasal septum, high-arched palate, low frontal hairline, and small, posteriorly angulated ears with prominent crura are the craniofacial features that are commonly encountered. Brachydactyly is char- actristic. Other manifestations may include mild cuta- neous syndactyly between the second and third fingers and, in some cases, broad triangular-shaped duplicated halluces [Reardon and Winter, 1994; Cohen, 2000a]. *Correspondence to: I. Teshima, Ph.D., Department of Pedia- tric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. E-mail: ikuko.teshima@sickkids.ca Received 9 August 2001; Accepted 6 February 2002 DOI 10.1002/ajmg.10400 ß 2002 Wiley-Liss, Inc.