Fine mapping of X-linked clasped thumb and mental retardation (MASA syndrome) in Xq28

The MASA syndrome is an X-linked disorder with mental retardation, spastic paraparesis, and adducted thumbs as the most characteristic features. We performed linkage analysis, using Xq28 markers, on a large MASA syndrome family. The maximum lodscore was 6.37 at 0 recombination for DXS52 and 5.99 at 0 recombination for DXS305. Crossovers were demonstrated between the disorder and DXS455. Clinical and linkage data from this family further support the hypothesis that the MASA syndrome and X-linked hydrocephalus are allelic disorders.     

The MASA syndrome: A new heritable mental retardation syndrome

Two Mexican-American children of West Texas are described: a brother and sister with a similar pattern of malformation. They have in common a tetrad of Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs. Besides these two sibs, who were available for study, it is known that a total of seven members of this kindred, six males and one female, spanning three generations, have been similarly affected. Although all members of this family come from the same ethnic background, consanguinity has been denied. The mode of inheritance cannot be firmly established at this time. It is in our opinion most compatible with that of an X-linked recessive gene with phenotypic expression in only one female due to unfavorable Lyonization. Other possibilities exist which cannot be entirely excluded. These include an autosomal dominant mutation with incomplete penetrance in at least three obligatory carrier females. Another possible mechanism is that of an autosomal recessive gene, since all members of this pedigree are of the same Mexican ancestry (Fig. 1. II-1, III-3, III-6). Because all affected members exhibit the four cardinal features of this disorder: Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs, wc wish to refer to this heritable condition as the MASA syndrome until the basic defect is further characterized.     

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.     

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.     

A new X linked recessive syndrome of mental retardation and mild dysmorphism maps to Xq28.

Efforts to understand the genetic basis of mental retardation are greatly assisted by the identification of families with multiple relatives with mental retardation that clinical geneticists encounter in the routine practice of their profession. Here we describe a linkage study of a four generation family in which X linked recessive mental retardation (XLMR) is associated with minor dysmorphism and premature death of the affected males. Microsatellite based polymorphic loci evenly spaced over the entire X chromosome were used initially to detect linkage to Xq28. Further analysis identified a haplotype of Xq28 markers bounded proximally by locus DXS1113 and distally by DXS1108 that cosegregated with XLMR in this family. Two point lod scores > 3.0 provided strong evidence that the gene locus responsible for XLMR in this family is within this 7 Mb region of Xq28. The minor anomalies noted in some affected males were not distinctive enough to suggest a unique syndrome. None of our patients had features of the Waisman-Laxova syndrome or the PPM-X syndrome. The possibility of allelism with any of the five other non-specific XLMR syndromes (MRX3, MRX16, MRX25, MRX28, and MRX41) mapped to Xq28 could not be excluded. While the recognition of a gene responsible for this disorder needs much additional work, multiple female relatives at risk in this family benefit immediately from knowing their genotype and heterozygotes will have the opportunity to undergo prenatal diagnosis.     

Barth syndrome: Clinical features and confirmation of gene localisation to distal Xq28

Barth syndrome is an X-linked disorder characterised by cardioskeletal myopathy of variable severity usually fatal in childhood, and neutropenia. We ascertained a large pedigree with affected males in 3 generations. All affected males had dilated cardiomyopathy, with endocardial fibroelastosis (EFE) in some. The locus for Barth syndrome in this family was found to be closely linked to DXS52 (z = 2.78, θ = 0.0). The family was non-recombinant for DXS52 in distal Xq28, but recombinant for DXS374 which maps proximal to DXS52. This localised Barth syndrome distal to DXS374, confirming a previous localisation to distal Xq28. As yet there is no evidence for genetic heterogeneity of Barth syndrome. © 1993 Wiley-Liss, Inc.     

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.     

Linkage of nonspecific X-linked mental retardation to Xq21.31.

Mental retardation unassociated with the Fragile X syndrome accounts for up to 60% of patients with X-linked mental retardation. In this investigation, we report on a family with mild non-specific X-linked mental retardation (MRX) without other apparent phenotypic abnormalities. Linkage analysis on 27 relatives using 18 polymorphic markers spanning the X-chromosome demonstrated close linkage to DXYS1 with a peak LOD score of 2.14 at a theta of 0. Numerous families with various types of MRX have now been studied by other investigators using molecular genetic techniques. In addition to the family described in this report, a number of these have demonstrated linkage to the DXYS1 locus. These data suggest that a gene for mental retardation may exist in the region of DXYS1. Alternatively, this area of the X-chromosome may harbor multiple different but closely linked genes which cause the various types of MRX.     

Novel X-linked mental retardation syndrome with short stature maps to Xq24

Microdeletions in the 22q11 region are associated with a wide range of overlapping phenotypes. The main manifestations of the syndrome include palatal anomalies such as cleft palate or velopharyngeal insufficiency, conotruncal heart defects, hypocalcemia, immune disorders, and minor facial anomalies. Because of the wide variability, facial changes appear to be the most constant manifestation of the syndrome and characteristic for informed physicians. The purpose of this study is to report the preliminary results of a detailed analysis of anthropometric data (35 measurements) in 15 patients (7 females and 8 males between 5 and 38 years of age, all white Europeans) with a 22q11 microdeletion. Objective anthropometric study showed that 19 measurements and 7 indexes were significantly different between 22q11 patients and normative database. The typical face showed a short forehead with an anterior vertical excess. Downslanting eyes and large binocular width were the most common anomalies in the orbital area. The nose showed anomalies with a large root, a short tip, and a narrow alar base. There was a narrowing of the mouth and thin lips. Ears were small and slightly disharmonic for the children. Statistical comparison between children (10 cases) and adults (5 cases) showed that craniofacial assessment was more demonstrative in children than in adults.     

Emery-Dreifuss muscular dystrophy: linkage to markers in distal Xq28.

Emery-Dreifuss muscular dystrophy (EMD) is characterised by (1) early contractures of the Achilles tendons, elbows, and postcervical muscles, (2) slowly progressive muscle wasting and weakness with a predominantly humeroperoneal distribution in the early stages, and (3) cardiomyopathy with conduction defects and risk of sudden death. Inheritance is usually X linked recessive but can be autosomal dominant. Family linkage studies have mapped X linked EMD to the distal long arm of the X chromosome but precise genetic localisation has been hampered by the rarity of this condition. We report three new families with X linked Emery-Dreifuss muscular dystrophy studied with DNA markers from Xq27-qter and three previously published families typed for additional markers. No recombination was observed with the red/green cone pigment locus, RGCP (lod score, Z = 2.46), the factor VIII coagulant gene locus, F8C (Z = 6.39), or with DXS115 (Z = 4.94). Two recombinants were observed which mapped EMD distal to DXS15 (DX13) and DXS52 (St14) respectively. Multipoint linkage analysis gave odds exceeding 200:1 for EMD being distal to these markers. A multipoint analysis incorporating published data gave the map cen-DXS304-9cM-DXS15-3cM-DXS52-2 cM-(RGCP,EMD)-3cM-F8C-2cM-DXS115 with odds of 120:1 in favour of a location for EMD between DXS52 and F8C as compared to the next best position distal to F8C.     

MASA syndrome: clinical variability and linkage analysis

We report on a family with three males with MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs). One patient demonstrated spastic paraplegia and psychomotor retardation but no adducted thumbs. The described family underlines the clinical variability in MASA syndrome. DNA studies confirm linkage to DNA markers of the Xq28 region. Analysis of published cases with hereditary spastic paraplegia (HSP), where linkage studies have been carried out, emphasizes the clinical variability in MASA syndrome and other types of HSP, thus making a definite diagnosis in single cases often impossible.     

A family with mental retardation, variable macrocephaly and macro-orchidism, and linkage to Xq12-q21.

A family with X linked inheritance of mental retardation (XLMR) is presented. There are 10 mentally retarded males and two affected females in two generations. There are four obligatory carriers, one of whom is described as "slow". Most affected males show macrocephaly and macro-orchidism, which are typical signs of the fragile X syndrome, but have been tested cytogenetically and by analysis of the FMR1 gene and do not have this syndrome. However, some normal males in the family also exhibit macro-orchidism and macrocephaly. Linkage analysis using markers derived from the X chromosome indicates that the causative gene in this family is located in the proximal long arm of the X chromosome, in the interval Xp11-q21. Maximum lod scores of 2.96 with no recombination were found at three loci in Xq13-q21: DXS1111, DXS566, and DXS986. Recombination was observed with DXS1002 (Xq21.31) and DXS991 (Xp11.2), loci separated by about 30 Mb. Although isolation of the gene in this family will be difficult because of the size of the region involved, the localisation should be helpful in investigating other similar families with XLMR, macrocephaly, and macro-orchidism not attributable to FMR1.     

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.     

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.     

Keipert syndrome (Nasodigitoacoustic syndrome) is X-linked and maps to Xq22.2-Xq28

Keipert syndrome is a rare condition comprising sensorineural deafness associated with facial and digital abnormalities. To date, Keipert syndrome has been reported in six male patients including two sib pairs; however the genetic basis of Keipert syndrome is yet to be elucidated. We report on the diagnosis of Keipert syndrome in the nephew of the brothers in the first report of Keipert syndrome, with a pedigree consistent with X-linked recessive inheritance. Linkage analysis using microsatellite markers along the X-chromosome suggests that the gene for Keipert syndrome is located in the region Xq22.2-Xq28. We postulate the Keipert syndrome is caused by a novel gene at Xq22.2-Xq28.     

MASA syndrome: new clinical features and linkage analysis using DNA probes.

We describe a two generation family in which two males have the X linked recessive MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs). A third male in this family died at the age of 15 years from congenital hydrocephalus. In the present family cerebral abnormalities are reported for the first time. Linkage analysis confirms the chromosome localisation at Xq28. A crossover between the coagulation factor VIII locus (F8C) and MASA syndrome, but not with DXS52 and DXS305, locates the gene on the same side of F8C as DXS52 and DXS305. The possible relationship between MASA syndrome and X linked hydrocephalus is discussed.     

Tentative assignment of gene for oto-palato-digital syndrome to distal Xq (Xq26–q28)

Detailed physical mapping of oto-palato-digital (OPD) syndrome gene on the X-chromosome was attempted on a family of 3 generations with 2 affected men. Although the result remains statistically non-significant, it indicates that the OPD-I gene might be located on the distal Xq.     

Dyskeratosis congenita: three additional families show linkage to a locus in Xq28.

Dyskeratosis congenita (DC) is a rare inherited disorder with most families being of the X linked recessive type. We describe three families which show linkage to the marker DXS52 on Xq28. The combined maximum lod score was 2.00 at zero recombination. This is further evidence that the X linked DC gene is located at Xq28 and brings the reported maximum lod score for DC and DXS52 to 5.33 at zero recombination fraction, with a supporting recombination fraction interval of 0.00-0.10.