X‐linked mental retardation: vanishing boundaries between non‐specific (MRX) and syndromic (MRXS) forms

Abstract

This review covers the history and nosology of X-linked mental retardation (XLMR) in which the following, largely clinically based, subclassification was used: fragile X syndrome (FRAXA), syndromic forms (MRXS) and non-specific forms (MRX). After the discovery of the FMR2 gene at the FRAXE site, 10 MRX genes have been identified in the last 6 years. A short description is given of the strategies used to identify the genes that cause mental retardation (MR). Furthermore, their potential functions and the association with MR will be discussed. It is emphasized that mutations in several of these MR genes can result in non-specific, as well as in syndromic forms of XLMR. Present findings stress the importance of accurate clinical evaluation. Most considerably, genotype-phenotype correlation studies of affected individuals in XLMR families with MRX gene mutations are necessary to define the criteria of MRX vs MRXS subclassification.

The Börjeson–Forssman–Lehman syndrome (BFLS, MIM #301900)

“…Some of these mutations, 1,5 experience with mutation screening tells us that there are no known familial cases with clinically diagnosed BFL syndrome where mutations in the PHF6 gene were not found. This, together with the identification of the PHF6 mutation in the original BFLS family 5,10 suggests that unlike many other XLMR syndromes 11 BFLS is not genetically heterogeneous. However, this does not mean that clinical and molecular diagnoses are well aligned as PHF6 mutation pickup rate in clinically diagnosed individuals with BFLS (predominantly isolated cases, 20/25) is relatively low, 5/25 cases (20%).…”

“…1 -3,5,7,8 Among these are 13 patients with a positive family history, including the original family described by M Börjeson, H Forssman and O Lehmann in 1962, 10 and six isolated cases. These mutations are summarized in Table 1.…”

Molecular and Comparative Genetics of Mental Retardation

“…This is because of ably because the phenotype depends on chance somatic both practical difficulties in mapping human phenomutations during brain development (Gilmore et (Table 2), the distinction between the two cate-X-linked MR syndromes for which the genes remain gories may not be as meaningful as originally proposed elusive. However, only 80 OMIM entries described (see discussion in Frints et al 2002). X-linked MR disorders (syndromes and nonspecific) for For RSK2 (RPS6KA3), the phenotype difference is which genes have not been identified (Table 1, X-linked explained by allele type and severity.…”

Monogenic X-linked mental retardation: Is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations

“…In fact, as discussed below for several other XLMR genes (ARX, OPHN1, PQBP1), the boundaries between syndromic and nonsyndromic forms are vanishing. 18 In terms of genetic counselling and etiological diagnosis, these results were however rather depressing. Almost all of the novel genes were found mutated in only one or two of the 80 large MRX families, and accounted for only a minority of families in which the segregating MR locus was mapped in the corresponding region of the X chromosome.…”