Genetic heterogeneity in X-linked agammaglobulinemia complicates carrier detection and prenatal diagnosis

X-linked agammaglobulinemia (XLA) is a severe antibody deficiency disease reflecting an arrest of B lymphocyte differentiation at the level of precursor B cells. The disease is inherited in an X-linked recessive mode. In a single eight-generation pedigree the XLA gene was mapped to the Xq21.3-Xq22 area of the X chromosome. The data establish close linkage of the XLA locus to the DXS17 restriction fragment length polymorphic (RFLP) marker locus (the lod score exceeding 6 at phi = 0). A series of RFLP markers around the DXS17 locus provided an RFLP haplotype of use in genetic counselling within this pedigree. In one other pedigree a phenotypically identical disease was inherited but was accompanied by a high frequency of recombination with the DXS17 locus, which made localisation of the gene at the DXS17 locus highly unlikely (lod score less than -3). This genetic heterogeneity complicates genetic counselling within particular pedigrees, especially when the localization of the XLA gene involved in those pedigrees has not been established.     

A new restriction fragment length polymorphism at the DXS101 locus allows carrier detection in a family with X linked agammaglobulinaemia.

The gene responsible for X linked agammaglobulinaemia (XLA) lies in Xq22 and has recently been identified as atk. DXS101 is a polymorphic locus which is closely linked to the disease locus. In this report we describe the identification, by pulsed field gel electrophoresis, of a new polymorphism at the DXS101 locus with a predicted heterozygosity of 4.9%. Despite this low value, we show how this polymorphism has been important in carrier status determination in a family with XLA where assessment was not possible by other means.     

X linked Charcot-Marie-Tooth disease (CMTX1): a study of 15 families with 12 highly informative polymorphisms.

X linked dominant Charcot-Marie-Tooth disease (CMTX1) has previously been localised to Xq13-21. Fifteen families were studied using 12 highly informative polymorphisms in the pericentric region of the X chromosome. Phase known recombinations in these families localise the X linked dominant CMT gene to the region distal to DXS106 (Xq11.2-12) and proximal to DXS559 (Xq13.1). These markers flank approximately 2 to 3 Mb of DNA to which GJB1 and CCG1 have already been mapped. A recent report of mutations in the GJB1 gene in subjects with CMTX1 makes this a strong candidate gene.     

Refining the genetic location of the gene for X linked hydrocephalus within Xq28.

The most common inherited form of hydrocephalus, X linked hydrocephalus (HSAS), is characterised by mental retardation, adducted thumbs, and spastic paraplegia. Genetic analysis has mapped the locus for HSAS to subchromosomal band Xq28 within a region of approximately 2 megabases of DNA. In order to refine the location of the disease gene we have conducted genetic linkage analysis with Xq28 marker loci in four additional HSAS families. A lod score of 4.26 with polymorphic marker DXS52 (St14) confirms the linkage of HSAS to Xq28. Identification of a recombination event between the HSAS gene and Xq28 loci F8C and DXS605 (2-19) reduces the size of the interval likely to contain the disease locus to about 1.5 megabases, the distance between DXS605 and DXS52. The locus for neural cell adhesion molecule, L1CAM, maps within this interval and therefore represents a candidate gene for HSAS.     

Multipoint linkage mapping of the Xq25-q26 region in a family affected by the X-linked lymphoproliferative syndrome

We have performed, in a large Swiss family, a study of linkage between various DNA markers in the Xq24-27 region and the locus for the X-linked lymphoproliferative syndrome (XLP). Our results indicated that the marker DXS37 in Xq25-q26 is genetically linked to the XLP syndrome. The multipoint linkage analysis showed that the disease locus is distal to DXS11, but proximal to the hypoxanthine phosphoribosyl-transferase gene (HPRT).     

Localisation of a new gene for non-specific mental retardation to Xq22-q26 (MRX35).

Non-specific mental retardation (MR) is a condition in which MR appears to be the only consistent manifestation. The X linked form (MRX) is genetically heterogeneous. We report clinical, cytogenetic, and linkage data on a family with X linked non-specific MR. Two point and multi-point linkage analysis with 18 polymorphic markers, covering the entire chromosome, showed close linkage to DXS1001 and DXS425 with a maximal lod score of 2.41 at 0% recombination. DXS178 and the gene for hypoxanthine phosphoribosyl-transferase (HPRT), located in Xq22 and Xq26 respectively, flank the mutation. All other chromosomal regions could be excluded with odds of at least 100:1. To our knowledge there is currently no other non-specific MR gene mapped to this region. Therefore, the gene causing MR in this family can be considered to be a new, independent MRX locus (MRX35).     

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.     

Mapping of DFN2 to Xq22

Non-syndromic X-linked deafness is a rare form of genetic deafness accounting for a small proportion of all hereditary hearing loss. It is both clinically and genetically heterogeneous and five loci have been described to date but only two of these have been mapped. DFN2 represents a locus for congenital profound sensorineural hearing loss that has yet to be mapped. We describe a four generation family with this phenotype in which female carriers have a mild/moderate hearing loss affecting the high frequencies. The mutant gene has been mapped to Xq22 using polymorphic microsatellite markers. A maximum two point lod score of 2.91 at theta = 0 was observed with a fully informative dinucleotide repeat at COL4A5, and flanking recombinations were observed at DXS990 and DXS1001.      

X linked neonatal myotubular myopathy: one recombination detected with four polymorphic DNA markers from Xq28.

A three generation family with X linked myotubular myopathy (MTM1) was studied with several polymorphic markers from the distal long arm of the X chromosome. A recombination between the disease gene and four markers (loci DXS52, DXS134, DXS15, F8C) from the Xq28 cluster was detected. A new polymorphic marker (U6.2) defining the locus DXS304 in the Xq27-28 region proximal to the Xq28 cluster did not show any recombination with MTM1. These results suggest the following order of loci in distal Xq: cen-DXS42-DXS105-(DXS304, MTM1)-(DXS52, DXS134, DXS15, F8C)-tel.     

Localisation of two candidate genes for mental retardation using a YAC physical map of the Xq21.1-21.2 subbands.

Genetic studies in families with X linked mental retardation have suggested the location of several MR genes in the human q21 region. Since the establishment of cloned resources is an essential step towards the cloning of genes involved in inherited diseases, we built a yeast artificial chromosome (YAC) contig and an STS map of this part of the X chromosome. The contig, which extends from PGK1 in Xq13.3 to DXS1002 in Xq21.2, consists of 30 YACs mapped with 21 markers and spans about 6 Mb. The YAC contig was used as a framework to localise several previously known genes and CEPH/Genethon polymorphic markers, as well as to construct a physical map of the region surrounding one of these genes. We recently localised a presumed MR locus to the region flanked by DXS233 (proximal) and CHM (distal). In the present work, the zinc finger gene, ZNF6, has been shown to lie within this region and to be highly expressed in brain, making it a good candidate MR gene. Similarly the VDAC1 gene has been mapped between DXS986 and DXS72 and its candidate gene status for the Allan-Herndon-Dudley syndrome is discussed.     

X linked neonatal centronuclear/myotubular myopathy: evidence for linkage to Xq28 DNA marker loci.

We have studied the inheritance of several polymorphic Xq27/28 DNA marker loci in two three generation families with the X linked neonatal lethal form of centronuclear/myotubular myopathy (XL MTM). We found complete linkage of XLMTM to all four informative Xq28 markers analysed, with GCP/RCP (Z = 3.876, theta = 0.00), with DXS15 (Z = 3.737, theta = 0.00), with DXS52 (Z = 2.709, theta = 0.00), and with F8C (Z = 1.020, theta = 0.00). In the absence of any observable recombination, we are unable to sublocalise the XLMTM locus further within the Xq28 region. This evidence for an Xq28 localisation may allow us to carry out useful genetic counselling within such families.     

Androgen insensitivity with mental retardation: a contiguous gene syndrome?

We present data to suggest the existence of a mental retardation (MR) locus at Xq11.2-q12 between DXS1 and DXS905, identified in two subjects with complete androgen insensitivity syndrome (CAIS) and MR. Androgen insensitivity syndrome is a disorder of male sexual differentiation caused by a defect in the androgen receptor (AR) gene (Xq11-q12). Two subjects with CAIS resulting from a complete deletion of the AR gene have previously been reported, one of whom also has MR. We have identified another mentally retarded person with a complete deletion of the AR gene. The deletion in the two patients with CAIS and MR extends past the AR gene and includes several marker loci both proximal and distal to the AR gene, the limits of the deletions being DXS1 and DXS905. The deletions in the CAIS patients who do not have MR do not include any of the markers outside the AR gene itself. These data suggest that located close to the AR gene is a gene which is implicated in non-specific MR.     

Further evidence localising the gene for Hunter''s syndrome to the distal region of the X chromosome long arm.

Cytogenetic re-evaluation of a fibroblast cell line from a female Hunter's syndrome case with a balanced X;autosome translocation, which had previously been reported to have a breakpoint in Xq26 to Xq27, showed the breakpoint to be either between Xq27 and Xq28 or within Xq28. The normal X chromosome was preferentially inactivated, supporting the view that the translocation had disrupted the Hunter gene. The new localisation is now in full agreement with our previous linkage work and other published data. Results of further linkage studies using probes defining the loci DXS86, DXS144, DXS100, DXS102, DXS105, F8C, and DXS134 are also consistent with our original conclusion that the Hunter locus lies within the distal region of the X chromosome long arm.     

X linked spastic paraplegia (SPG2): clinical heterogeneity at a single gene locus.

X linked hereditary spastic paraplegia is a rare condition that has been divided into two forms (the pure spastic form and the complicated form) as a function of clinical course and severity. A gene for pure hereditary spastic paraplegia (SPG2) has been mapped to the proximal long arm of the X chromosome (Xq21) by linkage to the DXS17 locus, while a gene for a complicated form of the disease has been mapped to the distal long arm by linkage to the DXS52 locus (Xq28). Here we report on the mapping of a gene for complicated hereditary spastic paraplegia to the Xq21 region by linkage to the probe S9 at the DXS17 locus (Z = 5 at theta = 0.04) in a three generation pedigree. Multipoint linkage analysis supports the distal location of the disease gene with respect to the DXYS1-DXS17 block (cen-DXYS1-DXS3-DXS17-SPG2-tel). The observation of a complicated form of spastic paraplegia mapping to Xq21 raises the difficult issue of variable phenotypic expression, allelic heterogeneity, or even close proximity of two genes for hereditary spastic paraplegia in this region. However, since our study provides clinical evidence for intrafamilial heterogeneity in complicated X linked spastic paraplegia, the present data support the hypothesis of variable clinical expression of a single gene at the SPG2 locus, as previously suggested for SPG1. Finally, we report here what we believe to be the first evidence of clinical expression in heterozygous carriers, a feature that is relevant to genetic counselling in at risk females.     

Mapping of X chromosome inversion breakpoints [inv(X)(q11q28)] associated with FG syndrome: A second FG locus [FGS2]?

FG syndrome is an X‐linked condition comprising mental retardation, congenital hypotonia, macrocephaly, distinctive facial changes, and constipation or anal malformations. In a linkage analysis, we mapped a major FG syndrome locus [FGS1] to Xq13, between loci DXS135 and DXS1066. The same data, however, clearly demonstrated genetic heterogeneity. Recently, we studied a French family in which an inversion [inv(X)(q12q28)] segregates with clinical symptoms of FG syndrome. This suggests that one of the breakpoints corresponds to a second FG syndrome locus [FGS2]. We report the results of fluorescence in situ hybridization analysis performed in this family using YACs and cosmids encompassing the Xq11q12 and Xq28 regions. Two YACs, one positive for the DXS1 locus at Xq11.2 and one positive for the color vision pigment genes and G6PD loci at Xq28, were found to cross the breakpoints, respectively. We postulate that a gene might be disrupted by one of the breakpoints. Am. J. Med. Genet. 95:178–181, 2000. © 2000 Wiley‐Liss, Inc.     

Smith-Fineman-Myers综合征基因定位于Xq25

目的　定位 Ｓｍｉｔｈ Ｆｉｎｅｍ ａｎ Ｍｙｅｒｓ 综合征基因,为分离该基因奠定基础。方法　应用覆盖 Ｘ染色体全长的、具有多态性的短串联重复序列（ Ｓ Ｔ Ｒ） 对 Ｘ 染色体进行扫查,确定致病基因所在区域和与致病基因连锁的 Ｓ Ｔ Ｒ 位点,再对该位点两侧的 Ｓ Ｔ Ｒ 位点进行分析,确定致病基因的精确位置。结果　用２０个覆盖 Ｘ 染色体全长的、具有多态性的 Ｓ Ｔ Ｒ 位点对该综合征患者家系中的１３ 个能明确提供连锁分析信息的家系成员进行分析,发现位于 Ｘｑ２５ 上的 Ｄ Ｘ Ｓ１００１ 与致病基因紧密连锁,最大两点ｌｏｄｓ 得分为３０１（θ＝ ０） ,对 Ｄ Ｘ Ｓ１００１ 两侧的 Ｓ Ｔ Ｒ 分析证实,该致病基因位于 Ｄ Ｘ Ｓ１００１ 区域,单体型分析表明该致病基因位于 Ｄ Ｘ Ｓ８０６４ 和 Ｄ Ｘ Ｓ８０５０ 之间,区域为１４６ｃ Ｍ。结论　 Ｓｍｉｔｈ Ｆｉｎｅｍ ａｎ Ｍｙｅｒｓ 综合征基因,位于 Ｘｑ２５ 上的 Ｄ Ｘ Ｓ８０６４ 和 Ｄ Ｘ Ｓ８０５０ 之间的１４６ｃ Ｍ 区域,该基因的定位为分离该基因奠定了基础。     

Failure to establish linkage on the X chromosome in 301 families with schizophrenia or schizoaffective disorder

The hypothesis that a gene for susceptibility to psychosis (specifically in the X-Y homologous class) is located on the sex chromosomes has been proposed. Such a gene would account for the excess of sex chromosome anomalous males and females in populations of patients with psychosis, a tendency towards concordance by sex within families, and sex differences associated with psychosis and its underlying brain pathology. In earlier studies we observed small positive LOD scores in Xp11, and in a more recent and larger cohort of 178 sibling pairs, a peak multipoint nonparametric LOD score of 1. 55 at the locus DXS8032 in Xq21. The present study with a new set of markers extended the cohort to 301 ill sibling pairs and their parents. Despite the increase in sample size, the LOD score did not increase. A peak NPL of 1.55 was observed at the locus DXS1068 in proximal Xp, a region remote from the previous report. Separating families into those who were more likely to have X chromosome inheritance (maternal with no male to male transmission) did not yield stronger findings. In spite of the evidence that psychosis is related to a sex-dependent dimension of cerebral asymmetry, it is concluded that no consistent linkage of schizophrenia to the X chromosome can be demonstrated. In the context of the general failure of replication of linkage in psychosis, the possibility that the genetic predisposition to psychosis is contributed to by epigenetic modification rather than variations in the nucleotide sequence has to be considered.     

Bridging markers defining the map position of X linked hypophosphataemic rickets.

Hypophosphataemic rickets is commonly an X linked dominant hereditary disorder associated with a renal tubular defect in phosphate transport and bone deformities. The gene causing this disorder has been mapped to Xp22.31----p21.3 by using cloned human X chromosome sequences identifying restriction fragment length polymorphisms (RFLPs) in linkage studies of affected families. The hypophosphataemic rickets gene locus (HPDR) was previously mapped distal to the X linked polymorphic locus DXS41 (99.6) but its position in relation to the distal loci DXS43 (D2) and DXS85 (782) was not established. In order to obtain a precise mapping of the disease locus in relation to these genetic loci, additional affected families informative for these X linked markers have been investigated. The combined results from the two studies have established linkage with the loci DXS41 (99.6) and DXS43 (D2); peak lod score for DXS41 (99.6) = 7.35, theta = 0.09, and peak lod score for DXS43 (D2) = 4.77, theta = 0.16. Multilocus linkage analysis mapped the hypophosphataemic rickets gene distal to the DXS41 (99.6) locus and proximal to the DXS43 (D2) locus, thereby revealing two bridging genetic markers for the disease.     

Linkage studies and deletion screening in choroideremia.

Fourteen families with choroideremia (TCD) have been examined for linkage to nine genetic markers located on the proximal long arm of the X chromosome. Linkage to three markers (DXYS1, DXS72, DXS3) located in Xq21 was found with a four point lod score of 8.25. No evidence of submicroscopic deletions was observed using DXS233 and DXS232, both thought to lie within about 1 Mb of the TCD gene.     

Linkage relationships between DXS105, DXS98, and other polymorphic DNA markers flanking the fragile X locus.

We report on linkage data between DXS105, DXS98, the locus for the fragile X syndrome (FRAXA), and 3 other polymorphic loci that flank the FRAXA locus. An analysis was undertaken to determine the relative positions of DXS105 and DXS98 and to test the assignment of DXS105 to a location proximal and closely linked to FRAXA. In this study of fragile X fra(X) syndrome families, the DXS105 locus was calculated to be proximal to FRAXA with a maximum lod score of 10.36 at theta = 0.08. DXS105 was also shown to be closely linked to the gene for factor IX (F9)(Z = 11.84 at theta = 0.08) and to DXS98 (Z = 4.91 at theta = 0.04). The order of the loci proximal to FRAXA is most likely centromere-factor IX-DXS105-DXS98-FRAXA-telomere. The use of DXS105 and DXS98 in clinical investigations should significantly increase the accuracy of risk assessment in informative fragile X families.