New X-linked syndrome of mental retardation, gynecomastia, and obesity is linked to DXS255.

We describe 14 males from 3 successive generations in a family who have X-linked mental retardation (XLMR), obesity, gynecomastia, speech difficulties, emotional lability, tapering fingers, and small feet. Linkage analysis using markers spread along the X chromosome demonstrated a gene localisation close to the centromere. Maximum lod scores for markers near the centromere, all at theta = 0.00, were 1.36 for DXS72, and 1.46 for DXYS1. The closest flanking markers which showed recombination were DXS84 and DXS94, defining the physical localisation within Xp21.1-q22. DXS255 was fully informative with lod-1 confidence interval for theta of 0.00-0.12. Clinical findings and linkage data in this family distinguish it from the B?rjeson-Forssman-Lehmann syndrome and other previously described XLMR syndromes.     

X-linked retinoschisis is closely linked to DXS41 and DXS16 but not DXS85

A linkage study was carried out in nine families with 24 males affected by X-linked recessive retinoschisis (RS), using three polymorphic DNA probes from the distal segment of Xp. Close linkage of the disease locus with markers DXS41 (probe p99-6) and DXS16 (pXUT23) was found, confirming the location of the RS gene on the distal short arm of the X chromosome. Lod scores for linkage with DXS85 (probe 782) were negative.     

A form of X-linked mental retardation with marfanoid habitus

A kindred has been studied in which mental retardation and marfanoid clinical features are present in several individuals. The pedigree is consistent with X-linked recessive inheritance. Four affected males aged 12-18 years and four obligate carriers have been identified. Clinical findings in the 4 affected males included a tall slender habitus (3) (the fourth was tall but muscular), a long-narrow face (3), large head (4), highly arched palate (4), small mandible (4), abnormal speech (4), hypernasal voice (3), joint hyperextensibility (3), borderline to large testes (3), pectus excavatum (2), atrial septal defect (1), and a double row of teeth (1). Mental retardation (4) ranged from mild to severe; abnormal behavior included hyperactive and aggressive behavior (2), autistic-like (1) and jovial behavior (1). One and possibly two, males had absence of the corpus callosum. Chromosome studies on all were normal; no marker X was observed. We believe this family probably represents a new form of X-linked mental retardation.     

Study of X-linked mental retardation (XLMR): Summary of 61 families in the Miami Greenwood study

The initial goal of this study was to localize as many genes as possible that lead to syndromic and non-specific XLMR. More recently, this goal has been redefined to include narrowing these localizations and cloning specific genes. In the last 5 years, 61 families have participated in this study; 34 have a projected or actual lod score greater than 2.0. Restudy of 12 families reported previously has been a particularly productive aspect of this study and has led to clinical redefinition and new or improved localization of most of these syndromes. Five possible new XLMR syndromes have been identified. Five large families with non-specific XLMR have been regionally localized. Since many XLMR conditions are based on only 1 or 2 family reports, one of the major purposes of this summary is to provide clinical data on the study families so that collaborative projects can be undertaken with other centers that have similar families. © 1996 Wiley-Liss, Inc.     

X-linked mental retardation exhibiting linkage to DXS255 and PGKP1: a new MRX family (MRX14) with localization in the pericentromeric region

Gene localization was determined by linkage analysis in a large French family with X-linked mental retardation (MRX). Seven living affected males were clinically studied and the clinical picture was characterized by moderate to severe mental handicap with poor secondary speech acquisition. Seizures, slight microcephaly, simian crease, anteverted pinnae, and macroorchidism were observed in some patients only. Linkage analysis revealed no recombination between the MRX gene and two loci: DXS255 at Xp11.22 (Zmax = 3.31 at θ= 0.00) and PGKP1 at Xq11.2-q12 (Zmax = 3.08 at 9 = 0.00). One recombination was observed between the gene and the two loci DXS164 at Xp21.2 and DXS441 at Xq13.3, respectively. These results suggested gene localization in the pericentromeric region of the X chromosome, and the LOD scores justified assignment of the symbol MRX14 to this family.     

A new X-linked mental retardation (XLMR) syndrome with late-onset primary testicular failure, short stature and microcephaly maps to Xq25-q26

X-linked mental retardation (XLMR) is a heterogeneous disorder with both syndromic and non-syndromic forms. Here we describe the clinical and molecular characterisation of a family with a syndromic form of XLMR with hypogonadism and short stature. We investigated a family in which four male members in two generations presented with hypergonadotrophic hypogonadism associated with development of small and abnormal testes. In two of the males, late-onset testicular ascent was noted. In addition, all affected males had short stature (<0.4th centile) and mild learning difficulties and three out of the four had microcephaly. Karyotypes were normal and endocrine investigations confirmed primary testicular failure. The phenotype segregated as an X-linked trait. Haplotype and genetic two-point linkage analysis with 22 microsatellites excluded the whole X chromosome except for a region on Xq25-Xq27 encompassing 13.7Mb with a maximum LOD score of 1.1 for marker DXS8038 at theta=0.05. One family previously described as having XLMR with hypogonadism and short stature maps to the same X chromosome region implicated in our family. However, the more severe mental retardation, muscle wasting and tremor described in this other family would suggest that our family is affected by a novel XLMR syndrome.     

A new X-linked mental retardation syndrome

We have studied a three-generation family with 11 moderately to severely retarded males and three mildly retarded females (presumably manifesting carriers). The patients have a phenotype different from that of all other previously described types of X-linked MR (XLMR). These include short stature, macrocephaly, "coarse" facial appearance including prominent forehead and supraorbital ridges, hypertelorism, broad nasal tip with anteverted nostrils, and thick lips. All postpubertal males had macroorchidism (volume greater than 25 ml). Chromosomes were normal including fragile X analysis. X-ray findings of skull, spine, and hands were normal. The intellectually normal relatives do not resemble their affected relatives except for increased head size and testicular size. These findings suggest a new variant of XLMR different from fragile X-linked MR, the Coffin-Lowry syndrome, and other XLMR conditions.     

Normal male carriers in the fra(X) form of X-linked mental retardation (Martin-Bell syndrome)

Evidence for the transmission of X-linked mental retardation through normal male carriers is reviewed in 6 kindreds. In these pedigrees we identified 15 unaffected males who likely had passed the gene on through their daughters. Fifty-one mentally retarded grandsons or great grandsons descended from these male carriers. In total, these males had 50 daughters with only 2 of them being of low intelligence. Two of the male carriers were recently identified through fra(X)- positive results in their mentally normal daughters. Among the sibs of these males, mentally retarded brothers were found in 3 families. This was unexpected since earlier observations suggested that the risk for mental retardation among sibs of nonmanifesting carriers is exceedingly low.     

Unique X-linked mental retardation syndrome with fingertip arches and contractures linked to Xq21.31

We studied 10 members of a 4 generation Missouri kindred with a dominant mental retardation syndrome with increasing severity in males. The 21 year-old propositus presented with severe mental retardation, microcephaly, asymmetric face, exotropia, hypogonadism, joint hypermobility, rocker bottom feet, and 10 low digital arches. Two brothers and a male cousin had similar features. The mother, sister, niece, maternal aunt, female cousin, and grandmother were examined and each had 8 to 10 low digital arches. Five of the women had exotropia and one had pes cavus feet. Chromosome analysis for fragile X in multiple relatives was normal. To determine the likelihood that this was an X-linked syndrome. DNA from relatives was hybridized to probes which detect 13 different loci spanning the X-chromosome. A peak LOD score of 2.78 at theta equal to 0.0 was calculated for the syndrome locus and DXYS1 (pDP34). The more distal Xq loci showed increasing recombination with the syndrome locus. These results are consistent with location for this syndrome near Xq21.31, the chromosomal locus for DXYSI.     

MECP2 is highly mutated in X-linked mental retardation

Following the recent discovery that the methyl-CpG binding protein 2 (MECP2) gene located on Xq28 is involved in Rett syndrome (RTT), a wild spectrum of phenotypes, including mental handicap, has been shown to be associated with mutations in MECP2. These findings, with the compelling genetic evidence suggesting the presence in Xq28 of additional genes besides RabGDI1 and FMR2 involved in non-specific X-linked mental retardation (MRX), prompted us to investigate MECP2 in MRX families. Two novel mutations, not found in RTT, were identified. The first mutation, an E137G, was identified in the MRX16 family, and the second, R167W, was identified in a new mental retardation (MR) family shown to be linked to Xq28. In view of these data, we screened MECP2 in a cohort of 185 patients found negative for the expansions across the FRAXA CGG repeat and reported the identification of mutations in four sporadic cases of MR. One of the mutations, A140V, which we found in two patients, has been described previously, whereas the two others, P399L and R453Q, are novel mutations. In addition to the results demonstrating the involvement of MECP2 in MRX, this study shows that the frequency of mutations in MECP2 in the mentally retarded population screened for the fragile X syndrome is comparable to the frequency of the CGG expansions in FMR1. Therefore, implementation of systematic screening of MECP2 in MR patients should result in significant progress in the field of molecular diagnosis and genetic counseling of mental handicap.     

A new X linked mental retardation (XLMR) syndrome with short stature, small testes, muscle wasting, and tremor localises to Xq24-q25

METHODS—A large family is described in which mental retardation segregates as an X linked trait. Six affected males in three generations were studied by linkage and clinical examination.
RESULTS—Characteristic clinical features include short stature, prominent lower lip, small testes, muscle wasting of the lower legs, kyphosis, joint hyperextensibility, abnormal gait, tremor, and decreased fine motor coordination. Affected subjects also had impaired speech and decreased attention span. A carrier female was mildly affected. A similar disorder was not found on review of our XLMR Database of 124 syndromes. Linkage analysis of 37 markers resulted in a lod score of 2.80 at DXS1212 and 2.76 at DXS425. The limiting markers were DXS424 and DXS1047. Ten of 124 XLMR syndromes and eight of 58 MRX families overlap this region.
CONCLUSIONS—In summary, this family appears to have a new XLMR syndrome localising to Xq24-q25.


Keywords: X linked mental retardation; Xq24-q25; syndrome     

Localization of non-specific X-linked mental retardation gene (MRX73) to Xp22.2

Clinical and molecular studies are reported on a family (MRX73) of five males with non-specific X-linked mental retardation (XLMR). A total of 33 microsatellite and RFLP markers was typed. The gene for this XLMR condition was been linked to DXS1195, with a lod score of 2.36 at theta = 0. The haplotype and multipoint linkage analyses suggest localization of the MRX73 locus to an interval of 2 cM defined by markers DXS8019 and DXS365, in Xp22.2. This interval contains the gene of Coffin-Lowry syndrome (RSK2), where a missense mutation has been associated with a form of non-specific mental retardation. Therefore, a search for RSK2 mutations was performed in the MRX73 family, but no causal mutation was found. We hypothesize that another unidentified XLMR gene is located near RSK2.     

Cloning and characterization of DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1

In several families with non-specific X-linked mental retardation (XLMR) linkage analyses have assigned the underlying gene defect to the pericentromeric region of the X chromosome, but none of these genes have been isolated so far. Here, we report on the cloning and characterization of a novel gene, DXS6673E, that maps to Xq13.1, is subject to X-inactivation and is disrupted in the 5' untranslated region by a balanced X;13 translocation in a mentally retarded female. The DXS6673E gene is highly conserved among vertebrates and its expression is most abundant in brain. It encodes a hydrophilic protein of 1358 amino acids (aa) that does not show sequence homology to other known proteins. A segment of this protein consisting of neutral and hydrophobic aa with a proline residue in every second position may represent a transmembrane domain. Almost complete sequence identity was found between the 3' end of the DXS6673E gene and two expressed sequence tags (ESTs) and between the 5' end of the DXS6673E gene and a third EST. Moreover, weaker sequence similarity was observed between coding regions and two other ESTs.      

Linkage mapping of a nonspecific form of X-linked mental retardation (MRX53) in a large Pakistani family

Nonspecific X-linked mental retardation is a nonprogressive, genetically heterogeneous condition that affects cognitive function in the absence of other distinctive clinical manifestations. We report here linkage data on a large Pakistani family affected by a form of X-linked nonspecific mental retardation. X chromosome genotyping of family members and linkage analysis allowed the identification of a new disease locus, MRX53. The defined critical region spans approximately 15 cM between DXS1210 and DXS1047 in Xq22.2-26. A LOD score value of 3.34 at no recombination was obtained with markers DXS1072 and DXS8081.     

X-linked mental retardation: A study of 7 families

Seven families with X-linked mental retardation (MR) have been studied clinically and cytogenetically. All affected males in six of the families were found to have a fragile site on Xq in a number of their peripheral lymphocytes. The fragile site was not seen in any of the affected males in the seventh family. The affected males in the six families with the fragile X had a syndrome characterized by a variable degree of MR, macro-orchidism, a characteristic repetitive, jocular speech, normal body proportions, and large jaws and ears. The fragile X chromosome could only be detected in a proportion of female carriers and its frequency in females was found to be correlated with their mental status and to be inversely correlated with their age.