Manifestations and linkage analysis in X‐linked autoimmunity‐immunodeficiency syndrome

The clinical findings of a kindred with an X‐linked disorder are characterized by autoimmune polyendocrinopathy, enteropathy with villous atrophy, chronic dermatitis, and variable immunodeficiency. Linkage analysis was performed on 20 members of the affected kindred to determine the location of the responsible locus. Informative recombinations limited the region to an approximate 20 cM interval bordered by DXS1055 and DXS1196/DXS1050. Multipoint analysis generated a lod score >3 for the region contained between DXS8024 and DXS8031. The candidate region includes the Wiskott‐Aldrich syndrome (WAS) locus. Evaluation of the Wiskott‐Aldrich syndrome protein gene by single strand conformational analysis, heteroduplex analysis, and direct sequencing of the 12 exons in an affected male and two carrier females revealed no abnormalities. We conclude that this kindred has an X‐linked disorder, distinct from WAS, that results in autoimmunity and variable immunodeficiency. The responsible locus maps to the pericentromeric region Xp11.23 to Xq21.1. Am. J. Med. Genet. 90:390–397, 2000. © 2000 Wiley‐Liss, Inc.     

Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia by linkage analysis

Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia was previously performed by the direct histological analysis of fetal skin obtained by late second trimester fetoscopy. The recent gene mapping of the locus for the disorder to the region of Xq11-21.1 now permits the indirect prenatal diagnosis of the disorder by the method of linkage analysis, based on closely linked marker loci, during the first trimester of pregnancy. We report the prenatal diagnosis of a male fetus with a high probability of the disorder by a linkage analysis utilizing restriction fragment length polymorphisms at the DXS159, PGK1, and DXS72 loci, from a DNA sample obtained by a chorionic villus biopsy at 9 weeks gestation. After further counseling, the pregnancy was terminated but the diagnosis could not be confirmed by histological analysis, even though analysis of skin samples by light and electron microscopy showed lack of hair germs, primary dermal ridges, and sweat gland primordia, due to the early developmental stage of the fetus. The use of DNA-based linkage analysis now offers the opportunity for an earlier diagnosis of X-linked hypohidrotic ectodermal dysplasia by a method other than fetal skin sampling. However, families must also fully understand the present limitations of the method prior to undertaking the procedure.     

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.     

X-linked myotubular myopathy: a linkage study

Two families with the congenital X-linked infantile form of myotubular myopathy have been investigated by linkage analysis using markers from the X-chromosome. Linkage was found at the locus Xq28 (with DXS52). The analysis gave a peak lod score of 2.41 at the recombination fraction zero. Free recombinations (theta = 0.50) were seen using the markers DXS84, DXS14 and DXS146 from the p arm of the X-chromosome. Since the disorder is very rare, it is important to add cumulative linkage data from the few families that do exist.     

Smith-Fineman-Myers综合征与X连锁核蛋白基因的连锁分析

目的 明确Smith-Fineman-Myers综合征（Smith-Fineman-Myers syndrome,SFMS)与X连锁核蛋白(X-linked unclear protein,XNP）基因之间的连锁关系。方法 采用聚合酶链反应结合变性聚丙烯酰胺凝胶电泳方法，分析SFMS家系中各成员XNP基因内多态位点基因型。结果 两个多态位点中，XNPSTR1有多态，家系分析结果表明XNP基因与SFMS致病基因之间存在重组。结论 XNP基因不是导致中国山东SFMS家系的致病基因，SFMS存在位点异质性。     

X-linked Dyggve-Melchior-Clausen syndrome

Ten affected males studied from four generations of a Colombian family with Dyggve-Melchior-Clausen (DMC) syndrome are described. The ages of the affected males varied from 13 to 50 years and they presented with typical clinical and radiological manifestations of the syndrome. The association of normal intelligence and a clear X-linked recessive inheritance in this family is evidence of heterogeneity in the Dyggve-Melchior-Clausen syndrome. In agreement with previous reports for DMC dwarfism, this new form has normal mucopolysaccharide excretion.     

Fragile X syndrome: linkage analysis in black and white populations

Eleven white families and 10 black families have been studied to detect racial differences in the linkage of DNA markers flanking the fragile X site (FRAXA). The differences in the recombination fractions for F9-FRAXA and DX13-FRAXA were not significant. The pair St14-FRAXA exhibited no difference between the two groups. Although the sample size was small, it would appear that these DNA markers can be used in black persons for prenatal diagnosis and genetic counseling. A larger group of families would be necessary to determine if 4D8 and cX55.7 will be equally useful since these appear to have lower heterozygote frequencies in the black population.     

Genetic linkage analysis in hereditary non-polyposis colon cancer syndrome.

Hereditary Non-polyposis Colon Cancer Syndrome (HNPCC) is the most common cause of familial colorectal cancer. Molecular genetic studies of HNPCC have shown evidence of locus heterogeneity, and mutations in four genes (hMSH2, hMLH1, hPMS1, and hPMS2) which encode components of the mismatch enzyme repair system may cause HNPCC. To determine the extent and nature of locus heterogeneity in HNPCC, we performed genetic linkage studies in 14 HNPCC families from eastern and north-western England. Linkage to hMLH1 was excluded in six families, each of which were likely to be linked to hMSH2 (lod score > 1.0 in each family and total lod score for all six families = 7.64). Linkage to hMSH2 was excluded in three families, each of which were likely to be linked to hMLH1 (lod score > 1.0 in each family and total lod score at hMLH1 for all three families = 3.93). In the remaining five families linkage to hMSH2 or hMLH1 could not be excluded. These results confirm locus heterogeneity in HNPCC and suggest that, in the population studied, most large families with HNPCC will have mutations in hMSH2 or hMLH1. We did not detect any correlation between clinical phenotype and the genetic linkage results, but a Muir-Torre syndrome family excluded from linkage to hMLH1 was likely to be linked to hMSH2 and showed microsatellite instability in a tumour from an affected relative.     

X-linked hyper IgM syndrome

Summary X-linked hyper IgM syndrome is largely caused by defects in the CD40L (CD154). The patients have low levels of IgG and have difficulty with respiratory infections as well as opportunistic infections. The morbidity of this syndrome is high; however, early diagnosis and therapy should reduce morbidity and mortality.     

X-linked lymphoproliferative disease: linkage studies using DNA probes

Linkage studies have been carried out with 28 X-linked polymorphic probes to try to locate the gene for X-linked lymphoproliferative disease (XLP). DNA from three families has been analysed, including three affected boys among 21 family members. None of the probes tested has been found to be linked to XLP. However, the data are recorded for the use of other workers on this rare disease.     

Use of linkage data obtained in single families: prenatal diagnosis of a new X-linked mental retardation syndrome.

Prenatal diagnosis was requested by an obligate carrier of a new syndrome of X-linked mental retardation. There was close linkage between the disease gene and the hypervariable VNTR marker DXS255 with a lod score of 4.82 at o = 0 (90% support interval 0.00-0.12). When the request for prenatal diagnosis was made, additional family members were examined, resulting in an amended lod score of 6.71 at o = 0.0 (90% support interval 0.00-0.09). There were no informative flanking markers at the time of the request for prenatal diagnosis; hence it proceeded by 2 point linkage analysis. The fetus was female with a carrier risk in the interval of 91-100%. Given the limitations of the mapping data available for this disorder at the time of the request, the options of accepting or rejecting this as a case for prenatal diagnosis were carefully considered. Whilst prenatal diagnosis based on fetal sexing would be sufficient to prevent the birth of an affected child, the magnitude of the known two-point lod score between DXS255 and the disease gene provided a means for diagnosis with an accuracy between 91 and 100%.     

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).     

Simpson-Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome

We report on another family with the so-called "gigantism-dysplasia syndrome", an X-linked condition characterized by pre- and postnatal overgrowth, characteristic face with apparent coarseness, dysplastic changes in several tissues, and mild intellectual impairment. This condition has been called the Golabi-Rosen syndrome; however, we agree that is the same entity as that described, in a milder form, by Simpson et al in 1975 and by Behmel et al in 1984. Therefore, we suggest that this entity be designated the Simpson-Golabi-Behmel syndrome. The manifestations in affected individuals suggest that this condition represents an X-linked encephalo-tropho-schisis syndrome.