American Journal of Medical Genetics 123A:140–147 (2003) A Genome-Wide Scan for Loci Predisposing to Non-Syndromic Cleft Lip With or Without Cleft Palate in Two Large Syrian Families Diego F. Wyszynski, 1 Hasan Albacha-Hejazi, 2 Mohammed Aldirani, 2 Moustafa Hammod, 2 Hikmat Shkair, 3 Ahmed Karam, 2 Jehad Alashkar, 2 Taura N. Holmes, 4 Elizabeth W. Pugh, 5 Kimberly F. Doheny, 5 Iain McIntosh, 6 Terri H. Beaty, 7 and Joan E. Bailey-Wilson 4 * 1 Genetics Program, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 2 Ibn Al-Nafees Hospital, Damascus, Syrian Arab Republic 3 Alhmra Street, Damascus, Syrian Arab Republic 4 Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland 5 Center for Inherited Disease Research, Johns Hopkins School of Medicine, Baltimore, Maryland 6 Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 7 Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland Non-syndromic cleft lip with/without cleft palate (CL/P) is a common, usually non-fatal birth defect of complex etiology. Several segregation analyses have demonstrated that genetic factors are important in the patho- genesis of CL/P, most likely through the in- teraction of several genes of modest effects. The aim of this study was to perform a genome- wide linkage analysis to identify/search for candidate gene loci for CL/P. We conducted a genome-wide search in two large, relatively isolated Syrian families, each one with a large number of cases with CL/P (18 in family 1 and 4 in family 2). A locus with a multipoint LOD score of 2.80 and a 2-point non-para- metric MLS LOD of 3.0 was detected on 17p13.1. Other chromosomal regions with multipoint LOD scores 1.2 (P  0.01) in- cluded 3p21.2, 4q32.1, and 7q34. These data indicate the possible presence of several susceptibility loci for CL/P and identify a strong candidate locus for this common birth defect on chromosome 17p13. Published 2003 Wiley-Liss, Inc. { KEY WORDS: linkage; oral clefts; CL/P; gene; genetics; susceptibility INTRODUCTION Non-syndromic cleft lip with or without cleft palate (CL/P [MIM 119530]) is a congenital anomaly of complex etiology that is usually non-fatal with modern treatment and affects approximately 1 in every 1,000 newborn babies [Mossey and Little, 2002]. Relatively few epide- miological studies on CL/P have been conducted in the Middle East. The reported overall birth prevalence of CL/P in most Middle Eastern countries is slightly higher than in European countries, but there is con- siderable variability [Azaz and Koyoumdjisky-Kaye, 1967; Borcbakan, 1969; Tal et al., 1974; Farhud et al., 1986; Salem et al., 1987; Srivastava and Bang, 1990; Kumar et al., 1991; Taher, 1992; Borkar et al., 1993; Zlotogora, 1997; Rajabian and Sherkat, 2000]. Birth prevalences of cleft lip and cleft palate have been reported to be as low as 0.37 per 1,000 births in Jews in Israel [Azaz and Koyoumdjisky-Kaye, 1967] and as high as 1.89 per 1,000 in Saudi Arabia [Borkar et al., 1993]. Birth prevalences of isolated cleft palate have been reported to be as low as 0.17 per 1,000 in Jews in Israel [Azaz and Koyoumdjisky-Kaye, 1967] and as high as 0.42 per 1,000 in Kuwait [Srivastava and Bang, 1990]. Middle Eastern societies, especially rural Arab popu- lations, are characterized by close family relationships and inbreeding rates are generally high. The proportion of consanguineous marriages ranges between 25% in Grant sponsor: National Institutes of Health; Grant number: N01-HG-65403; Grant sponsor: Massachusetts Center for Birth Defects Research and Prevention of the Massachusetts Depart- ment of Public Health; Grant sponsor: National Institute for Dental and Craniofacial Research of the National Institutes of Health (to THB and IM); Grant number: R01-DE-10293; Grant sponsor: Etiology grant of the Cleft Palate Foundation (to DFW). *Correspondence to: Dr. Joan E. Bailey-Wilson, NHGRI/NIH, Triad Technology Center, Suite 2000, 333 Cassell Drive, Balti- more, MD 21224. E-mail: jebw@nhgri.nih.gov Received 9 October 2002; Accepted 24 March 2003 DOI 10.1002/ajmg.a.20283 Published 2003 Wiley-Liss, Inc. y This article was prepared by a group consisting of both United States Government employees and non-United States Government employees, and as such is subject to 117U.S.C. Sec. 105.