American Journal of Medical Genetics 112:400–404 (2002) Clinical Report TM4SF2 Gene Involvement Reconsidered in an XLMR Family After Neuropsychological Assessment Marie Gomot, 1 * Nathalie Ronce, 1 Sabine Dessay, 1 Ramzi Zemni, 2 Anne-Dominique Ayrault, 1 Marie-Pierre Moizard, 1 Annie Nivelon, 3 Simone Gilgenkrantz, 4 Julliette Dourlens, 1 Vincent Des Portes, 2 Jamel Chelly, 2 and Claude Moraine 1 1 Service de Ge´ne´tique, INSERM 4316 CHU Bretonneau, Tours, France 2 INSERM Unite´129-ICGM, CHU Cochin, Paris, France 3 Service deGe´ne´tique, CHR,Dijon, France 4 Service deGe´ne´tique, CentreHospitalier, Nancy, France The TM4SF2 gene (localized at Xp11.4 be- tween the loci DXS564 and DXS556) has been found to be mutated in one MRX family. In order to define the corresponding behavior- al phenotype, global IQ and specific cogni- tive skills were assessed in seven males and three females of this family, independent of subject status. Mental retardation (MR) was mild in three patients and moderate in three others. Despite the broad variability of se- verity of MR, a cognitive profile specific to the MR in this family was documented. It was characterized by language disorder that was more marked in the articulatory component and spatial/verbal short-term memory dis- sociation with larger mnemonic span for spatial than for verbal cues. Linkage ana- lysis was then performed on the basis of the cognitively determined status. Recombina- tions were observed with the loci DXS556 at Xp11.4 and DXS441 at Xq13.2 (maximum LOD score ¼ 2.23 at u ¼ 0 for ALAS2). This localiza- tion region does not include the TM4SF2 gene that has been found mutated in both patients with MR and in one non-MR male subject of this family. The present results suggest two main hypotheses. First, TM4SF2 gene mutation could be involved in MR in this family, therefore representing accentu- ated intra familial phenotypic variability. Second, the structural particularity detect- ed in the TM4SF2 gene might reflect a rare polymorphism rather than a pathogenic mu- tation, with the gene responsible for MR in this family being therefore more likely to be searched for in the pericentromeric region of the X chromosome. ß 2002 Wiley-Liss, Inc. KEY WORDS: XLMR; cognitive profile; TM4SF2; linkage analysis; Xp11.4-Xq13.2 INTRODUCTION X-linked mental retardation (XLMR) is thought to occur at a frequency of 1/600 male births [Herbst and Miller, 1980], representing 3 – 10% of all cases of mental retardation [Anderson et al., 1996]. XLMR is usually divided into specific form (MRXS) in which MR is asso- ciated with specific physical phenotype or metabolic disorders, and nonspecific XLMR (MRX) without char- acteristic physical features [Neri et al., 1991]. The inci- dence of the nonspecific forms is estimated at 1/1,000 males. Linkage and epidemiological studies suggest that more than 30 different Xlinked-genes could be involved in the heterogeneous MRX group. The first twelve genes identified to date are involved in less than 15% of MRX multiplex families (Jamel Chelly, personal communica- tion). The MECP2 gene, which is mutated in Rett syndrome, is also probably responsible for 1% to 1.5% additional cases of MRX [Amir et al., 1999; Couvert et al., 2001]. Other MRX genes remain to be discovered. In the absence of specific physical features, neuro- psychology appears to be a useful tool to define specific phenotypes in families in which mutation in candidate genes are searched. We have recently identified the TM4SF2 gene as mutated in MRX families [Zemni et al., 2000]. The aim of this study is to report extensive Grant sponsor: Fondation pour la Recherche Me ´dicale; Grant number: ARS 2.14; Grant sponsor: INSERM; Grant sponsor: Association Franc ¸aise contre les Myopathies. *Correspondence to: Marie Gomot, Service de Ge ´ne ´tique, CHU Bretonneau, 2 bd Tonnelle ´, 37044 Tours Cedex, France. E-mail: m.gomot@chu-tours.fr Received 14 December 2001; Accepted 9 April 2002 DOI 10.1002/ajmg.10564 ß 2002 Wiley-Liss, Inc.