American Journal of Medical Genetics 129A:286–289 (2004) A Locus for Nonspecific X-Linked Mental Retardation Mapped to a 22.3 cM Region of Xp11.3-q22.3 Xiyu Zhang, Qiji Liu, Bingxi Chen, Chenhong Guo, Jiangxia Li, Guimin Gao, Yishou Guo, and Yaoqin Gong* Institute of Medical Genetics, Shandong University School of Medicine, Jinan, People’s Republic of China By using several microsatellite markers scattered along the X chromosome, we studied a Chinese family with nonspecific X-linked mental retarda- tion (MRX84) to search for a region including the MRX84 locus that was linked to the markers. Two-point linkage analysis demonstrated linkage between the disorder and several markers located at Xq22.2, with maximum LOD score Z max ¼ 2.41 at recombination fraction u ¼ 0 for DXS1191 and DXS1230, respectively. Recombination events were observed with flanking markers DXS8080 and DXS456, located at Xp11.3 and Xq22.3, respec- tively, and a region of approximately 22.3 cM was defined. Accordingly, markers distal to Xp11.3 and Xq22.3 segregated independently of the disease. The localized region observed in this Chinese family overlaps with 29 other MRX loci previously reported in Xp11.3-q22.3. These results should contribute to the identification of the disease gene for the MRX84 disorder. ß 2004 Wiley-Liss, Inc. KEY WORDS: X-linked nonspecific mental re- tardation (MRX); gene mapping; microsatellite markers; linkage analysis INTRODUCTION Mental retardation (MR) is a common and distressing clini- cal condition. Approximately 2 – 3% of the population has mild MR (intelligence quotient, IQ < 70), and 0.3% of individuals are severely handicapped (IQ < 50) [Chelly, 1999]. The observation that there are more affected males than females suggests that X-linked MR (XLMR) may be a major contributor to excess retardation in males. XLMR conditions are subdivided into five major classes [Neri et al., 1994], and nonspecific conditions (MRX) is an important class. MRX is defined as MR in males from a family with an X-linked pattern of inheritance, where affected males have no consistent phenotypic manifestations other than MR to distinguish them from unaffected males in the family [Kerr et al., 1991]. MRX is a very common disorder which affects 1 in 600 males [Chelly, 1999]. It is reported that MRX accounts for more than 2/3 of all XLMRs [Fryns et al., 2000]. Since MRX is clinically homogeneous and genetically heterogeneous, gene localization in large families has become the only means of distinguishing MRX conditions. MRX loci yielding a two-point LOD score >2.0 at recombination fraction y ¼ 0 are given a unique number, indicating that the MRX genes are clearly localized [Mulley et al., 1992]. The study of MRX is usually carried out through linkage analysis of one large MRX family. It is estimated that 76 MRX families have been reported so far and among them 69 MRX loci have been mapped on the X chromosome [Hamel et al., 2000]. So far, only nine MRX genes have been identified [Toniolo, 2000; Chelly and Mandel, 2001]. The following study was undertaken to localize the genetic region responsible in a Chinese family for segregation of MRX. The region identified attained a two-point LOD score of Z ¼ 2.41 > 2.0 at y ¼ 0, mapped to an approximately 22.3 cM region in Xp11.3-q22.3 and has been assigned the number MRX84. MATERIALS AND METHODS Clinical Report The pedigree of the affected Chinese family (Fig. 1), obtained from a Primary Genetic Disorders survey of Shandong Province P.R.C., showed the segregation of moderate to mild MR [Jiang, 1998] through two unaffected obligatory carrier females to three affected males in three generations. Obliga- tory carrier females did not exhibit any clinical manifestations. X-linked recessive inheritance is strongly suggested by the occurrence of MR exclusively in males and lack of male-to-male transmission. All affected males were born at term after normal pregnan- cies and had mild to moderate MR. They were all of short stature and III-2 had a broad forehead, but no characteristic pattern of anomalies was shared by all three patients. (The height of Chinese adult males is 170.7  5.9 cm (X  SD). Data come from National Survey on Body development in 1995. Chinese adults’ head circumference is 56.1  1.539 cm (X  SD), ranging from 54 to 58 cm). Individual III-1 had moderate MR (IQ ¼ 40). He was 39 years-old and 163 cm high (3–10% centile) [Shang et al., 2000]; his head circumference was 54 cm (5% centile) [Xiao et al., 1998]. Compared with normal Chinese adult males, his height was within the scope of normal males’ height but shorter than the average value his head circumference was on the edge of the critical range. Surgery was required to resolve a block of the urethral orifice 3 days after he was born. At one and a half years-old, he could walk and speak simple words. As an adult, he had poor memory and recognized the numbers from 1 to 10; he could do no calculations and could only complete simple physical labor. Individual III-2 had mild MR (IQ ¼ 58). He was 29-years-old and 166 cm high (10 – 25% centile); his head circumference was 54 cm (5% centile). He could walk when he was 1-year-old. He had poor ability to calculate and had been degraded many times in school. When grown-up, he could take care of himself. He could compute addition but not subtraction, and could Grant sponsor: The State Key Basic Research and Development Plan Program; Grant number: 2001CB510303; Grant sponsor: National Science Fund for Distinguished Young Scholars; Grant number: 30225020. *Correspondence to: Yaoqin Gong, Ph.D., Institute of Medical Genetics, Shandong University School of Medicine, 44 Wenhua West Road, Jinan, P.R.C., 250012. E-mail: gongyaoqin@yahoo.com Received 17 October 2002; Accepted 19 December 2003 DOI 10.1002/ajmg.a.30121 ß 2004 Wiley-Liss, Inc.