X-linked mental retardation with neonatal hypotonia in a French family (MRX15): Gene assignment to Xp11.22-Xp21.1

Linkage analysis was performed in a family with non-specific X-linked mental retardation (MRX 15). Hypotonia in infancy was the most remarkable physical manifestation. The severity of mental deficiency was variable among the patients, but all of them had poor or absent speech. Significant lod scores at a recombination fraction of zero were detected with the marker loci DXS1126, DXS255, and DXS573 (Zmax = 2.01) and recombination was observed with the two flanking loci DXS164 (Xp21.1) and DXS988 (Xp11.22), identifying a 17 cM interval. This result suggests a new gene localization in the proximal Xp region. In numerous families with non-specific X-linked mental retardation (MRX), the corresponding gene has been localized to the paracentromeric region in which a low recombination rate impairs the precision of mapping. © 1996 Wiley-Liss, Inc.     

A locus for nonspecific X-linked mental retardation mapped to a 22.3 cM region of Xp11.3-q22.3

By using several microsatellite markers scattered along the X chromosome, we studied a Chinese family with nonspecific X-linked mental retardation (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) = 2.41 at recombination fraction theta = 0 for DXS1191 and DXS1230, respectively. Recombination events were observed with flanking markers DXS8080 and DXS456, located at Xp11.3 and Xq22.3, respectively, 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.     

Localization of a gene for X-linked nonspecific mental retardation (MRX24) in Xp22.2–p22.3

Nonspecific X-linked mental retardation (MRX) includes several distinct genetic entities in which mental retardation is not associated with additional distinguishing physical changes. We report linkage data in a Spanish family with MRX, using polymorphic DNA markers distributed over the X chromosome. Two-point linkage analysis demonstrated close linkage between the MRX locus and DXS85 in Xp22.3 with a peak lod score of 2.28 at a Ø = 0.00. Analysis of multiple informative meioses suggested a localization of the MRX locus (MRX24) between DXS278 and DXS207. Multipoint linkage analysis resulted in a maximum LOD score of 2.45 at 3 cM proximal to DXS85, and allowed us to reject a localization of the MRX24 gene in all other regions from Xp21–Xqter. These findings localize the MRX24 gene in the chromosomal region Xp22.2–p22.3. © 1995 Wiley-Liss, Inc.     

Regional localization of two MRX genes to Xq28 (MRX28) and to Xp11.4-Xp22.12 (MRX33)

Two genes responsible for a nonspecific form of X-linked mental retardation (MRX28 and MRX33) were localized by linkage analysis with 40 highly polymorphic DNA markers situated along the entire the X chromosome. In family 1, the gene could be mapped within a 14-cM interval at Xq28, distal to the recombining marker DXS1113 (MRX28). The maximum LOD score was 2.75, with DXS52 at ϕ = .0. In family 2, the gene was localized within a 30-cM interval at Xp11.4-22.12 between the recombining markers DXS365 and MAOB, including the DMD gene (MRX33). Maximum LOD scores of 2.82 were obtained with markers DMD-STR49, DMD-DysII, CYBB, and DXS1068. © 1996 Wiley-Liss, Inc.     

X-linked nonspecific mental retardation (MRX16) mapping to distal Xq28: linkage study and neuropsychological data in a large family

A genetic linkage study was performed on a large four-generation family with variable nonspecific X-linked mental retardation (MRX16), speech abnormalities, and retardation of all milestones. Significant linkage was found in the Xq28 region with loci DXS52, DXS15, BGN, and DXS1108 with maximum LOD scores of 4.86, 4.01, 4.83, and 5.43, respectively, at theta = 0.00. Recombination was observed at the locus DXS1113, thus mapping the gene in an 8-Mb interval between this marker and the Xq telomere. Linkage intervals of three other MRX families overlap with this interval in Xq28 where the RABGDIA gene, mutated in the MRX41 and MRX48 families, is also located. In MRX3, MRX28, but also in MRX16, no alteration of RABGDIA has been found, thus suggesting the existence of at least two MRX genes in distal Xq28.     

Regional localization of two non-specific X-linked mental retardation genes (MRX30 and MRX31)

Two genes responsible for X-linked mental retardation have been localised by linkage analysis. MRX30 maps to a 28 cM region flanked by the loci DXS990 (Xq21.3) and DXS424 (Xq24). A significant multipoint lod score of 2.78 was detected between the loci DXS1120 and DXS456. MRX31 maps to a 12 cM region that spans the centromere from DXS1126 (Xp11.23) to DXS1124 (Xq13.3). Significant two-point lod scores, at a recombination fraction of zero, were obtained with the loci DXS991 (Zmax = 2.06), AR (Zmax = 3.44), PGK1P1 (Zmax = 2.06) and DXS453 (Zmax = 3.31). The MRX30 localisation overlaps that of MRX8, 13, 20 and 26 and defines the position of a new MRX gene on the basis of a set of non-overlapping regional localisations. The MRX31 localisation overlaps the localisations of many of the pericentromeric MRX loci (MRX, 1, 4, 5, 7, 8, 9, 12, 13, 14, 15, 17, 20, 22 and 26). There are now at least 8 distinct loci associated with non-specific mental retardation on the X chromosome defined, in order from pter to qter, by localisation for MRX24, MRX2, MRX10, MRX1, MRX30, MRX27, FRAXE and MRX3. © 1996 Wiley-Liss, Inc.     

Localization of a non-syndromic X-linked mental retardation gene (MRX80) to Xq22-q24

Isolated mental retardation is clinically and genetically heterogenous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. We report here a linkage analysis in a large family including 15 members, 6 of whom presenting X-linked non-syndromic mental retardation (MRX). Two-point linkage analysis using 23 polymorphic markers covering the entire X chromosome demonstrated significant linkage between the causative gene and DXS8055 with a maximum LOD score of 2.98 at theta = 0.00. Haplotype analysis indicated location for the disease gene in a 23.1 cM interval between DXS1106 and DXS8067. This MRX localization overlaps with 7 XLMR loci (MRX23, MRX27, MRX30, MRX35, MRX47, MRX53, and MRX63). This interval contains two genes associated with non-syndromic mental retardation (NSMR), namely the PAK3 gene, encoding a p21-activated kinase (MRX30 and MRX47) and the FACL4 gene encoding a fatty acyl-CoA ligase (MRX63). As skewed X-inactivation, an apparently constant feature in FACL4 carrier females was not observed in an obligate carrier belonging to the MRX family presented here, the PAK3 gene should be considered as the strongest candidate for this MRX locus.     

Mapping to distal Xq28 of nonspecific X-linked mental retardation MRX72: linkage analysis and clinical findings in a three-generation Sardinian family

Families with mentally retarded males found to be negative for FRAXA and FRAXE mutations are useful in understanding the genetic basis of X-linked mental retardation. According to the most recent data (updated to 1999), 69 MRX loci have been mapped and 6 genes cloned. Here we report on a linkage study performed on 20 subjects from a 4-generation Sardinian family segregating a non-specific X-linked recessive mental retardation (XLMR)(MRX72) associated with global delay of all psychomotor development. Five of 8 affected males have been tested for mental age, verbal and performance skills and behavioral anomalies; mental impairment ranged from mild to severe. Only minor anomalies were present in the affected subjects. Two-point linkage analysis based on 28 informative microsatellites spanning the whole X chromosome demonstrated linkage between the disorder and markers DXS1073 and F8c in Xq28 (maximum Lod score of 2. 71 at straight theta = 0.00). Multipoint linkage analysis confirmed the linkage with a Z(max) of 3.0 at straight theta = 0.00 at DXS1073 and F8c. Recombination in an affected male at DXS1073 and F8c allowed us to delimit centromerically and telomerically the region containing the putative candidate gene. The region, where MRX72 maps, overlaps that of another MRX families previously mapped to Xq28, two of which harbored mutations in GDI. Involvement of this gene was excluded in our family, suggesting another MRX might reside in Xq28.     

Localization of a non-specific X-linked mental retardation gene, MRX23, to Xq23-q24

More than 100 X-linked mental retardation syndromes have been described. We report the localization of the disease gene, MRX23, in one family to Xq23-24. Affected family members present with non- specific X-linked mental retardation with verbal disability (BDOAS 10, 1-100). MRX23 is tightly linked to the markers DXS1220 (Z = 3.76 at theta = 0.1) and DXS424 (Z = 3.9 at theta = 0.06). Multipoint linkage analysis, taking five loci (DXS1072-0.07-DXS1220-0.014-MRX23-0.01-DXS 424-0.08-DXS1001) at a time, gives a maximum LOD score of 6.7 between these two markers. The next most likely location, between DXS424 and DXS1001 is 120-fold less likely. Haplotype analysis also indicates the most likely location for the disease gene is between DXS1220 and DXS424.      

MRX8: an X-linked mental retardation condition with linkage to Xq21.

A family in which 6 males have X-linked mental retardation has been studied with polymorphic DNA probes. The males differ from unaffected males only in impaired intellect and in smaller head size. The gene that causes mental retardation in the family appears to be located in band Xq21 on the basis of linkage with 3 markers: DXS250, DXS345 and DXS3 (theta max = 0.00; Zmax = 1.6). A multipoint lod score of 2.36 was obtain with no recombination relative to DXS326 in Xq21. This family is considered to have nonspecific X-linked mental retardation and has been given the designation MRX8.     

Regional localization of a nonspecific X-linked mental retardation gene (MRX59) to Xp21.2-p22.2.

Linkage analysis was performed on a four-generation family with nonspecific mental retardation (MRX59). The five affected males, ranging in age from 2 years to 52 years, have a normal facial appearance and mild to severe mental impairment. Four obligate carriers are physically normal and not retarded. A maximum LOD score of 2.41 at straight theta = 0.00 was observed with the microsatellite markers, DMD45 in Xp21.2, DXS989 in Xp22.1, and DXS207 in Xp22.2. Recombinations were detected within the dystrophin gene (DMD) in one of the affected males and between DXS207 and DXS987 in Xp22.2 in one of the carriers. These recombinants define the proximal and distal boundaries of a candidate gene region. Genetic localization of this familial condition made prenatal diagnosis informative for one of the obligate carriers.     

Refined 2.7 centimorgan locus in Xp21.3-22.1 for a nonspecific X-linked mental retardation gene (MRX54).

Nonspecific X-linked mental retardation (MRX) is a heterogeneous condition in which mental retardation (MR) appears to be the only consistent manifestation. A large genetic interval of assignment obtained on individual families by linkage analysis, genetic, heterogeneity, and phenotypic variability usually are major obstacles to fine-map and identify the related disease genes. Here we report on a large Tunisian family (MRX54) with an MRX condition. X-linked recessive inheritance is strongly suggested by the segregation of MR through seven unaffected carrier females to 14 affected males in two generations. Two-point linkage analysis demonstrated significant linkage between the disorder and several markers in Xp21.3-22.1 (maximum LOD score Zmax = 3.56, recombination fraction 0 = 0 at DXS1202), which was confirmed by multipoint linkage analyses. Recombinant events observed with the flanking markers DXS989 and DXS1218 delineate a refined locus of approximately 2.7 cM in accordance with the physical distance between these two markers. The small interval of assignment observed in this family overlaps not only with nine large MRX loci previously reported in Xp21.3-22.1 but also with two inherited microdeletions in Xp21.3-22.1 involved in nonspecific MR. Although the involvement of several genes located in the Xp21.3-22.1 region cannot be ruled out, data reported in this study could be used as a starting point for the search of such gene(s).     

Mapping to distal Xq28 of nonspecific X‐linked mental retardation MRX72: Linkage analysis and clinical findings in a three‐generation Sardinian family

Families with mentally retarded males found to be negative for FRAXA and FRAXE mutations are useful in understanding the genetic basis of X‐linked mental retardation. According to the most recent data (updated to 1999), 69 MRX loci have been mapped and 6 genes cloned. Here we report on a linkage study performed on 20 subjects from a 4‐generation Sardinian family segregating a non‐specific X‐linked recessive mental retardation (XLMR)(MRX72) associated with global delay of all psychomotor development. Five of 8 affected males have been tested for mental age, verbal and performance skills and behavioral anomalies; mental impairment ranged from mild to severe. Only minor anomalies were present in the affected subjects. Two‐point linkage analysis based on 28 informative microsatellites spanning the whole X chromosome demonstrated linkage between the disorder and markers DXS1073 and F8c in Xq28 (maximum Lod score of 2.71 at θ = 0.00). Multipoint linkage analysis confirmed the linkage with a Z_max of 3.0 at θ = 0.00 at DXS1073 and F8c. Recombination in an affected male at DXS1073 and F8c allowed us to delimit centromerically and telomerically the region containing the putative candidate gene. The region, where MRX72 maps, overlaps that of another MRX families previously mapped to Xq28, two of which harbored mutations in GDI. Involvement of this gene was excluded in our family, suggesting another MRX might reside in Xq28. Am. J. Med. Genet. 94:376–382, 2000. © 2000 Wiley‐Liss, Inc.     

Atrioventricular septal defect with pulmonary atresia in DiGeorge anomaly: Expansion of the cardiac phenotype

A gene responsible for X-linked mental retardation with macrocephaly and seizures (MRX38) in a family with five affected males in three generations was localized to Xp21.1–-p22.13 by linkage analysis. Recombination events placed the gene between DXS1226 distally and DXS1238 proximally, defining an interval of approximately 14 cM. A peak lod score of 2.71 was found with several loci in Xp21.1 (DXS992, DXS1236, DXS997, and DXS1036) at a recombination fraction of zero. The map intervals of 5 X-linked mental retardation loci, MRX2 (Xp22.1–p22.2), MRX19 (Xp22), MRX21 (Xp21.1–p22.3), MRX29 (Xp21.2–p22.1), and MRX32 (Xp21.2–p22.1), and two syndromal mental retardation loci, Partington syndrome (PRTS; Xp22) and Coffin-Lowry syndrome (CLS; Xp22.13–p22.2), overlap this region. As none of these display the same phenotype seen in the family reported here, this X-linked mental retardation locus may represent a new entity. © 1996 Wiley-Liss, Inc.     

Gene for non-specific X-linked mental retardation maps in the pericentromeric region

Linkage analysis was carried out in a large four-generation German family segregating for non-specific X-linked mental retardation. Affected males have moderate intellectual handicap. Speech delay, deviant behaviour, and hyperactivity have also been reported. Head circumference and testicular volumes are normal. Cytogenetic analysis failed to show evidence for fragile site or structural abnormality of the X chromosome. None of the obligatory carriers shows any clinical symptoms. Close linkage without recombination (lod scores 1.74 to 2.05) has been found between the disease locus (MRX1) and the polymorphic DNA loci DXS7 (Xp11.4-p11.3), MAOA (Xp11.3-p11.23), DXS255 (Xp11.22), and DXS159 (Xq12) suggesting that the gene responsible for the disease in this family maps in the pericentromeric region of the X chromosome. Linkage data obtained with the flanking marker loci OTC (Xp21.1) and DXS95 (Xq21.2-q21.3) also were compatible with this localization of the MRX1 gene. Close linkage to loci from Xp22, Xq22, Xq24-25, or Xq28 could be excluded.     

A gene for nonsyndromic X-linked mental retardation (MRX77) maps to Xq12-Xq21.33

Nonsyndromic X-linked mental retardation (MRX) is a highly heterogeneous condition in which mental retardation appears to be the only consistent manifestation. According to the most recent data, 77 MRX families with a lod score of >2 have been mapped and eight genes have been cloned. We hereby report on a linkage analysis performed on a Greek family with apparently nonsyndromic MRX. The affected males have moderate to severe mental retardation, severe speech problems, and aggressive behavior. Two-point linkage analysis with 26 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 27 Mb interval in Xq12-Xq21.33. The maximum LOD score was found for markers DXS1225, DXS8114, and DXS990 at 2.36, 2.06, 2.06, respectively at theta = 0.00. Recombination was observed for DXS983 at the proximal side and DXS6799 at the distal side. Nineteen other MRX families have been described with a partial overlapping disease gene interval in proximal Xq. No mutations were found in the MRX77 family for three known or candidate MRX genes, from this region OPHN1, RSK4, and ATR-X. These data indicate that the Xq12-Xq21.33 interval contains at least one additional MRX gene.     

Nonsyndromic X-linked mental retardation: mapping of MRX58 to the pericentromeric region.

An Austrian family with nonsyndromic X-linked mental retardation (MRX) is reported in which the obligatory carrier females are normal, and 5 affected males have mild to moderate mental retardation. Linkage analysis indicated an X pericentromeric localization, with flanking markers DXS989 and DXS1111 and a maximum multipoint LOD score of 2.09 (straight theta = 0) for the 7 cosegregating markers DXS1243, CybB, MAOB, DXS988, ALAS2, DXS991, and AR. MRX58 thus mapped within a 50-cM interval between Xp11.3 and Xq13.1 and overlapped with 23 other MRX families already described. This pericentromeric clustering of MRX families suggests allelism, with a minimum of 2 X-linked mental retardation (XLMR) genes in this region.     

Regional localization of a gene for nonspecific XLMR to Xp11.3-p11. 23 (MRX51) and tentative localization of an MRX gene to Xq23-q26.1.

Two families with nonspecific X-linked mental retardation (MRX) are presented. In the first family, MRX51, three male patients showed mild to borderline mental retardation. Multipoint linkage analysis yielded a maximal LOD score of 2.10 between markers DXS8012 and DXS1003, localizing the MRX51 gene at Xp11.3-p11.23. In the second family, XLMR7, three men showed moderate mental retardation (MR), and one possible female carrier had mild MR. Multipoint linkage analysis yielded an LOD score of 1.80 between markers DXS8063 and DXS1047, situating the disease gene at Xq23-q26.1. When the analysis was performed considering the affected female to be an expressing heterozygote carrier of the disease mutation, a maximal LOD score of 2.10 was found in the same region.     

Nonsyndromic X-linked mental retardation: Mapping of MRX58 to the pericentromeric region

An Austrian family with nonsyndromic X-linked mental retardation (MRX) is reported in which the obligatory carrier females are normal, and 5 affected males have mild to moderate mental retardation. Linkage analysis indicated an X pericentromeric localization, with flanking markers DXS989 and DXS1111 and a maximum multipoint LOD score of 2.09 (θ = 0) for the 7 cosegregating markers DXS1243, CybB, MAOB, DXS988, ALAS2, DXS991, and AR. MRX58 thus mapped within a 50-cM interval between Xp11.3 and Xq13.1 and overlapped with 23 other MRX families already described. This pericentromeric clustering of MRX families suggests allelism, with a minimum of 2 X-linked mental retardation (XLMR) genes in this region. Am. J. Med. Genet. 86:102–106, 1999. © 1999 Wiley-Liss, Inc.     

A gene for nonspecific X-linked mental retardation (MRX41) is located in the distal segment of Xq28

We report on a family in which non-syndromal mild to moderate mental retardation segregates as an X-linked trait (MRX41). Two point linkage analysis demonstrated linkage between the disorder and marker DXS3 in Xq21.33 with a lod score of 2.56 at θ = 0.0 and marker DXS1108 in Xq28 with a lod score of 3.82 at θ = 0.0. Multipoint linkage analysis showed that the odds for a location of the gene in Xq28 vs Xq21.33 are 100:1. This is the fourth family with non-specific X-linked mental retardation with Xq28-qter as the most likely gene localization. © 1996 Wiley-Liss, Inc.