Am. J. Hum. Genet. 71:1195–1199, 2002 1195 Duane Radial Ray Syndrome (Okihiro Syndrome) Maps to 20q13 and Results from Mutations in SALL4, a New Member of the SAL Family Raidah Al-Baradie, 1,3,* Koki Yamada, 2,3,* Cynthia St. Hilaire, 2 Wai-Man Chan, 2 Caroline Andrews, 2,3 Nathalie McIntosh, 2,† Motoi Nakano, 2,3,‡ E. Jean Martonyi, 4 William R. Raymond, 5 Sada Okumura, 6 Michael M. Okihiro, 6 and Elizabeth C. Engle 1,2,3 Departments of 1 Neurology and 2 Genetics, Children’s Hospital Boston, and 3 Harvard Medical School, Boston; 4 W. K. Kellogg Eye and Vision Research Center, University of Michigan, Ann Arbor; 5 Department of Ophthalmology, Madigan Army Medical Center, Tacoma, WA; and 6 Straub Clinic and Hospital, Honolulu Duane syndrome is a congenital eye movement disorder characterized most typically by absence of abduction, restricted adduction, and retraction of the globe on attempted adduction. Duane syndrome can be coinherited with radial ray anomalies as an autosomal dominant trait, referred to as “Okihiro syndrome” or “Duane radial ray syndrome” (DRRS). We ascertained three pedigrees with DRRS and mapped their disease gene to a 21.6-cM region of chromosome 20 flanked by markers D20S888 and D20S102. A new member of the SAL family of proposed C 2 H 2 zinc finger transcription factors, SALL4, falls within the region. Mutation analysis of SALL4 in the three pedigrees revealed one nonsense and two frameshift heterozygous mutations. SALL4 represents the first identified Duane syndrome gene and the second malformation syndrome resulting from mutations in SAL genes and likely plays a critical role in abducens motoneuron development. Several forms of congenital ophthalmoplegia are hy- pothesized to result from errors in the development of the ocular cranial nuclei (Nakano et al. 2001). The most common of these, Duane syndrome (MIM 126800 and MIM 604356), is characterized by restricted or absent abduction and variably restricted adduction with re- traction of the globe on attempted adduction, and results from absence of the abducens (nVI) motoneurons and nerve, with sparing of the internuclear neurons (Hotch- kiss et al. 1980; Miller et al. 1982). Two Duane syn- drome loci (DURS1 and DURS2) have been mapped, but neither gene has been identified (Vincent et al. 1994; Appukuttan et al. 1999). Duane syndrome can be coin- herited with radial anomalies in an autosomal dominant fashion (fig. 1A). In affected individuals, radial dysplasia ranges from hypoplasia of the thenar eminence to ab- sence of the radial bone or forearm. Variable expression of sensorineural hearing loss and cardiac, renal, verte- bral, and lower extremity malformations can occur. De- Received June 25, 2002; accepted for publication July 29, 2002; electronically published October 22, 2002. Address for correspondence and reprints: Dr. Elizabeth C. Engle, Enders 551, Division of Genetics, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115. E-mail: engle@enders.tch .harvard.edu * These authors contributed equally to this work. † Present affiliation: Department of Biology, Brandeis University, Waltham, MA ‡ Present affiliation: Department of Plastic and Reconstructive Sur- gery, Oita Nakamura Hospital, Oita, Japan.  2002 by The American Society of Human Genetics. All rights reserved. 0002-9297/2002/7105-0019$15.00 scribed in the 1970s and referred to as “Okihiro syn- drome” or “Duane radial ray syndrome” (DRRS) (included in MIM 126800) (Okihiro et al. 1977; Tem- tamy and McKusick 1978; Appukuttan et al. 1999), this distinct disorder partially overlaps clinically with Townes-Brocks and Holt-Oram syndromes, as well as acroreno-ocular, oculo-otoradial, cervico-oculoacostic, and oculoauriculovertebral syndromes. To investigate the role that the DRRS gene plays in abducens development, we analyzed two white pedigrees and one Japanese pedigree (V, FN, and DA, respectively) segregating DRRS as an autosomal dominant trait with apparent full penetrance (fig. 1B–1D). The study was approved by Children’s Hospital Boston Review Board, and appropriate informed consent was obtained from all participants. The clinical features of pedigrees DA and FN have been described elsewhere (Okihiro et al. 1977; Chun et al. 2001). Of the 13 affected participants in the three families, 12 have Duane syndrome. Among them, the Duane syndrome phenotype can be unilateral or bilateral and includes individuals with marked or complete limitation of abduction with minimal or no limitation of adduction (Duane syndrome type 1) and individuals with marked or complete limitation of both abduction and adduction (Duane syndrome type 3). None of the participants had marked or complete lim- itation of adduction with minimal or no limitation of abduction (Duane syndrome type 2). The presence of more than one Duane syndrome type within a single pedigree was also described in a family whose disease gene maps to the DURS2 locus (Chung et al. 2000) and