Reply to Mandel

Abstract

To the Editor:On behalf of all the authors of our recent study (Rosenberg et al. 2004xHigh prevalence of SLC6A8 deficiency in X-linked mental retardation. Rosenberg, EH, Almeida, LS, Kleefstra, T, deGrauw, RS, Yntema, HG, Bahi, N, Moraine, C, Ropers, HH, Fryns, JP, deGrauw, TJ, Jakobs, C, and Salomons, GS. Am J Hum Genet. 2004; 75: 97–105Abstract | Full Text | Full Text PDF | PubMed | Scopus (116)See all References2004), we thank Dr. Mandel for his comments (Mandel 2004xComparative frequency of fragile-X (FMR1) and creatine transporter (SLC6A8) mutations in X-linked mental retardation. Mandel, JL. Am J Hum Genet. 2004; 75: 730–731Abstract | Full Text | Full Text PDF | PubMed | Scopus (6)See all References2004 [in this issue]), to which we fully subscribe, and we apologize for the misleading statement in our article. Indeed, SLC6A8 mutations, although probably more common than mutations in other known nonsyndromic X-linked mental retardation (MRX) genes except ARX, must be much less frequent than pathogenic CGG expansions in the FMR1 gene. As pointed out by Mandel (2004xComparative frequency of fragile-X (FMR1) and creatine transporter (SLC6A8) mutations in X-linked mental retardation. Mandel, JL. Am J Hum Genet. 2004; 75: 730–731Abstract | Full Text | Full Text PDF | PubMed | Scopus (6)See all References2004 [in this issue]), this is convincingly illustrated by the relative paucity of ARX mutations in nonselected cohorts of males with mental retardation (MR) (Gronskov et al. 2004xScreening of the ARX gene in 682 retarded males. Gronskov, K, Hjalgrim, H, Nielsen, IM, and Brondum-Nielsen, K. Eur J Hum Genet. 2004; PubMedSee all References2004). Mandel's second argument, which implies that mutation rates in X-linked genes can be inferred from their lengths and must be intrinsically much lower than the rate of CGG expansions in FMR1, is less compelling in view of the evidence for mutational hotspots in many disease genes, including ARX and PQBP1, a recent addition to the growing list of genes involved in MRX (Kalscheuer et al. 2003xMutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. Kalscheuer, VM, Freude, K, Musante, L, Jensen, LR, Yntema, HG, Gecz, J, Sefiani, A et al. Nat Genet. 2003; 35: 313–315Crossref | PubMed | Scopus (88)See all References2003). Therefore, the existence of another common but hitherto-unknown cause of nonsyndromic MR cannot be ruled out yet, even though ongoing large-scale mutation screening in regions known to carry many mutations (Ropers et al. 2003xNonsyndromic X-linked mental retardation: where are the missing mutations?. Ropers, HH, Hoeltzenbein, M, Kalscheuer, V, Yntema, H, Hamel, B, Fryns, JP, Chelly, J, Partington, M, Gecz, J, and Moraine, C. Trends Genet. 2003; 19: 316–320Abstract | Full Text | Full Text PDF | PubMed | Scopus (56)See all References2003) has so far failed to identify such a gene.Reliable estimation of the relative importance of SLC6A8 and other MRX genes in the etiology of MR will have to await systematic screening of large, unselected cohorts of patients with MR. So far, comprehensive studies of this kind have only been reported for a few genes, including FMR1 and ARX.