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PubMed1992

Waardenburg syndrome (WS) type I is caused by defects at multiple loci, one of which is near ALPP on chromosome 2: first report of the WS consortium.

Previous studies have localized the gene for Waardenburg syndrome (WS) type I to the distal portion of chromosome 2q, near the ALPP locus. We pooled linkage data obtained from 41 WS type I and 3 WS type II families which were typed for six polymorphic loci on chromosome 2q in order to refine the location of the WS locus (WS1) and evaluate the extent of genetic heterogeneity. In the course of this work, we developed diagnostic criteria for genetic and phenotypic studies. Our findings, based on two-locus and multilocus analysis using a linkage map established from reference pedigrees, suggest that there are two or more mutations causing WS, one of which (i.e., WS1) is located on chromosome 2q, between the ALPP and FN1 loci, at distances of 7.8 cM and 11.2 cM for each marker, respectively. The results also indicate that WS1 is responsible for the illness in approximately 45% of all families in this sample. However, the odds favoring this position over a location between ALPP and SAG are only 2:1 when alternate assumptions about the proportion of linked families are considered. We conclude that a more saturated map of this region of chromosome 2q, including highly polymorphic markers, will be needed to accurately distinguish linked families and, ultimately, isolate the mutant gene.

Alkaline Phosphatase↗

PubMed1992

The Wiskott-Aldrich syndrome: refinement of the localization on Xp and identification of another closely linked marker locus, OATL1.

The Wiskott-Aldrich syndrome (WAS) has previously been mapped to the proximal short arm of the X chromosome between the DXS14 and DXS7 loci. In this study, further segregation analysis has been performed using a newly identified WAS family as well as an additional marker probe, HOATL1. The results indicate close linkage between the WAS and OATL1 loci (Z = 6.08 at theta = 0.00) and localize the TIMP, OATL1, DXS255, and WAS loci distal to DXS146 and the OATL1 and WAS loci proximal to TIMP. These linkage data narrow the boundaries within which the WAS locus maps to the chromosomal region bracketed by TIMP and DXS146 and support the loci order Xpter-DXS7-TIMP-(OATL1, WAS, DXS255)-DXS146.

Alleles↗

PubMed1995

Linkage analysis in a Dutch family with X-linked recessive congenital stationary night blindness (XL-CSNB).

Linkage analysis has been performed in a large Dutch pedigree with X-linked recessive congenital stationary night blindness (CSNB) by utilizing 16 DNA markers from the proximal short arm of the human X chromosome (Xp21.1-11.2). Thirteen polymorphic markers are at least partially informative and have enabled pairwise and multipoint linkage analysis. For three loci, i.e. DXS228, the monoamine oxidase B gene and the Norrie disease gene (NDG), multipoint linkage studies have yielded maximum lod scores of > 3.0 at a recombination fraction of zero. Analysis of recombination events has enabled us to rule out the possibility that the underlying defect in this family is allelic to RP3; the gene defect could also be excluded from the proximal part of the region known to carry RP2. Linkage data are consistent with a possible involvement of the NDG but mutations in the open reading frame of this gene have not been found.

Chromosome Mapping↗

PubMed1988

Localization of DNA probes with tight linkage to the cystic fibrosis locus by in situ hybridization using fibroblasts with a 7q22 deletion.

Five DNA probes known to originate from the region 7q22-q31 were sublocalized by in situ hybridization to metaphase preparations of fibroblasts having besides a normal chromosome 7, a homologue 7 with an apparent interstitial deletion of a large part of band q22. A flow cytometric chromosome analysis confirmed a loss of material from one of the homologues of chromosome 7. Four of the probes, B79a, 7C22, metH, and pJ3.11, have been shown to be closely linked to the cystic fibrosis (CF) locus. We localized probes B79a and 7C22 to the part of 7q22 involved in the deletion, whereas metH and pJ3.11 could be assigned to band 7q31. Probe pJu28, for which polymorphisms have not yet been described, also appeared to derive from the latter band. Since pJ3.11 and metH are most tightly linked to the CF locus, this disease locus is indirectly assigned to 7q31. A comparison of our findings with linkage data suggests a discrepancy between genetic and physical distances in the region 7q22-q31.

Chromosome Banding↗

PubMed1989

Linkage analysis of the murine mos proto-oncogene on chromosome 4.

A linkage analysis of the murine Mos gene, which codes for the c-mos proto-oncogene, was performed in 88 backcross progeny of an interspecies cross of laboratory mice and Mus spretus. Linkage was tested for four different genes on mouse chromosome 4: Aco-1, Mup-1, b, and Ifb. The gene order (from centromere) with intervening percentage recombination is Mos-15.9 (+/- 3.9)-Aco-1-5.6 (+/- 2.4)-Mup-1-3.4 (+/- 1.9)-b-5.6 (+/- 2.4)-Ifb. These results confirm the previous assignment of Mos to chromosome 4 on the basis of segregation in somatic cell hybrids (D. Swan et al., 1982, J. Virol. 44: 752-754) and show furthermore that Mos and the Ifa/Ifb clusters are not tightly linked as a group of intronless genes, but are separated by a map distance of 30.6 +/- 4.9 recombination units. The linkage data obtained in the present study place Mos in a region compatible with the physical map (D. W. Threadgill and J. E. Womack, 1988, Genomics 3: 82-86).

Aconitate Hydratase↗

PubMed2001

Diagnostic misclassification reduces the ability to detect linkage in inflammatory bowel disease genetic studies.

BACKGROUND: Linkage data have now identified several inflammatory bowel disease (IBD) susceptibility loci but these data have not been consistently replicated in independent studies. One potential explanation for this is the possibility that patients enrolled in such studies may have been erroneously classified with respect to their diagnosis. AIMS: To determine the rate and type of misclassification in a large population of individuals referred for participation in an IBD genetics study and to examine the effect of diagnostic misclassification on the power to detect linkage. METHODS: The medical records of 1096 patients entered into an IBD genetics programme were reviewed using standardised diagnostic criteria. The original patient reported diagnoses were changed, if necessary, based on review, and the reasons for the change in diagnosis were recorded. To evaluate the effect of misclassification on linkage results, simulations were created with Gensim and analysed using Genehunter to evaluate a model for IBD inheritance. RESULTS: Sixty eight of 1096 (6.2%) individuals had a change in diagnosis from that originally reported. The majority of changes were patients with either Crohn's disease or ulcerative colitis who were determined not to have IBD at all. The principal reasons for changes to the original diagnosis were discordance between the patients' subjective reports of diagnosis and actual clinical history, endoscopic, or pathological results; a change in disease pattern over time; and insufficient information available to confirm the original diagnosis. A 10% misclassification rate resulted in 28.4% and 40.2% loss of power to detect a true linkage when using a statistical model for a presumed IBD locus with lambda(s) values of 1.8 and 1.3, respectively. CONCLUSIONS: Diagnostic misclassification occurs in patients enrolled in IBD genetic studies and frequently involves assigning the diagnosis of IBD to non-affected individuals. Even low rates of diagnostic misclassification can lead to significant loss of power to detect a true linkage, particularly for loci with modest effects as are likely to be found in IBD.

Chromosome Mapping↗

PubMed1989

Linked markers flanking the gene for multiple endocrine neoplasia type 2A.

The inherited cancer syndrome multiple endocrine neoplasia type 2A (MEN2A) has recently been mapped to chromosome 10. We have typed 29 families with this disorder with DNA markers from the pericentromeric region of chromosome 10. Two markers, RBP3 and MCK2, were tightly linked to the MEN2A gene at recombination fractions of less than 3%. Multipoint analysis of the linkage data suggests that the gene is located within a 3-cM interval defined by the markers RBP3/MCK2 on one side and TB14.34 on the other. No evidence for locus heterogeneity was detected in any of the 27 families from 14 countries who were informative for the markers tested. The data confirm and refine the original assignment and provide the basis for presymptomatic screening for this disorder.

Chromosome Mapping↗

PubMed2000

The IL9R region contribution in asthma is supported by genetic association in an isolated population.

Interleukin 9 (IL9) is involved in mast cell maturation and the enhancement of IgE production by B cells. Furthermore, linkage data in human and mice have suggested that IL9 may contribute to asthma. Since our genetic analysis of the 5q cytokine cluster did not support a genetic role for the IL9 gene, we became interested in the IL9 receptor gene (IL9R) in the pseudoautosomal region. We genotyped markers sDF2 and sDF1 close to the IL9R gene among 289 affected and 368 family-based controls. The results were studied by using linkage, transmission disequilibrium, association and homozygosity analyses. Linkage analyses remained negative, presumably because of our low power for linkage study. However, all the other analyses yielded evidence that the IL9R gene region may have a role in the development of asthma. The sDF2*10 allele was more frequently transmitted than untransmitted to asthmatic offspring (34 vs 16, pchi2 < or = 0.01), and it was found homozygotic among asthma patients more often than expected (Psimul2 = 0.009). Also, a specific X chromosomal haplotype, sDF2*10-sDF1*6 associated with asthma (40 vs 7, Pchi2 < 0.005, Psimul1 = 0.04).

Alleles↗

PubMed2000

Linkage to Gaucher mutations in the Ashkenazi population: effect of drift on decay of linkage disequilibrium and evidence for heterozygote selection.

The two most common Gaucher disease mutations in the Ashkenazi population, 1226A-->G and 84G-->GG in the glucocerebrosidase gene, are tightly linked to a marker in the nearby pyruvate kinase gene. This paper develops a simulation of the Ashkenazi population that considers the effects of selection and drift on the mutant allele frequency and the recombinant haplotype frequency over time. Although the fraction of mutants that are linked to the original marker decays exponentially on average, this expected value is not very likely to occur. Instead, due to random loss of the recombinant haplotype, a mutation has a significant probability of retaining complete linkage disequilibrium long after its origin, so there may be large errors in estimating the age of a mutation based on linkage data. The simulations show that the 1226G mutation probably originated between 40 and 1000 generations ago (1000 to 25,000 years ago), and the 84GG mutation probably originated between 50 and 4800 generations ago (1300 to 120,000 years ago). The recent origin of the 1226G mutation and its high current allele frequency provide strong evidence for heterozygote selection. New techniques and results developed in this paper have general applicability toward analyzing linkage disequilibrium near other mutations. For example, they potentially explain the unexpected pattern of linkage disequilibrium seen around the DeltaF508 mutation of the cystic fibrosis transmembrane conductance regulator gene.

Gaucher Disease↗

PubMed1993

Assignment of the norepinephrine transporter protein (NET1) locus to chromosome 16.

The norepinephrine transporter protein (NET) is the presynaptic reuptake site for norepinephrine and a site of action for several drugs with CNS effects, some of which are therapeutically useful and some of which are drugs of abuse. We used PCR with a somatic cell hybrid panel to obtain a provisional assignment to chromosome 16. We then typed a genetic polymorphism at the NET1 locus in three large multigenerational families and used linkage analysis to confirm the preliminary assignment and to refine the localization to 16q, near the HP locus. Finally, we typed the NET1 RFLP on the CEPH families and the additional linkage data localized NET1 to 16q13-q21, flanked by D16S71 (centromerically) and HP (telomerically).

Carrier Proteins↗

PubMed1985

Linkage analysis of a DNA polymorphism proximal to the Duchenne and Becker muscular dystrophy loci on the short arm of the X chromosome.

The inheritance of a restriction fragment length polymorphism (RFLP) detected by a cloned DNA sequence (p754) from the short arm of the X chromosome has been studied in 14 Duchenne muscular dystrophy kindreds and six Becker muscular dystrophy kindreds. The linkage data obtained suggest that both the DMD and BMD loci are located in the same region (p21) on the short arm of the X chromosome at a distance of about 15 to 20 cM from the 754 locus. Data from families informative for both the p754 and L1.28 polymorphisms suggest that p754 is closer to the disease loci than is L1.28.

Chromosome Mapping↗

PubMed1983

Dominant spinocerebellar ataxia: genetic counseling.

Dominantly inherited spinocerebellar ataxia (OPCA 1) poses a particular problem for genetic counseling due to late age of onset. Liability for disease using observed age of onset can be combined with HLA linkage data to provide revised estimates of risk for affection. Where data is informative, certain combinations may yield estimates which improve so rapidly with age that postponement of childbearing may become a strong consideration as an option.

Adolescent↗

PubMed1992

The autosomal dominant familial exudative vitreoretinopathy locus maps on 11q and is closely linked to D11S533.

Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is a hereditary disorder characterized by the incomplete vascularization of the peripheral retina. The primary biochemical defect in adFEVR is unknown. The adFEVR locus has tentatively been assigned to 11q by linkage studies. We report the results of an extended multipoint linkage analysis of two families with adFEVR by using five markers (INT2, D11S533, D11S527, D11S35, and CD3D) from 11q13-q23. Pairwise linkage data obtained in the two families were rather similar and hence have not provided evidence for genetic heterogeneity. The highest complied two-point lod score (3.67, at a recombination fraction of .07) was obtained for the disease locus versus D11S533. Multipoint analyses showed that the adFEVR locus maps most likely, with a maximum location score of over 20, between D11S533/D11S527 and D11S35, at recombination rates of .147 and .104, respectively. Close linkage without recombination (maximum lod score 11.26) has been found between D11S533 and D11S527.

Chromosome Mapping↗

PubMed1977

Human beta-glucuronidase: assignment of the structural gene to chromosome 7 using somatic cell hybrids.

beta-Glucuronidase (GUS) has become an important enzyme model for the genetic study of molecular disease, enzyme realization, and therapy, and for the biogenesis and function of the lysosome and lysosomal enzymes. The genetics of human beta-glucuronidase was investigated utilizing 188 primary man-mouse and man-chinese hamster somatic cell hybrids segregating human chromosomes. Cell hybrids were derived from 16 different fusion experiments involving cells from ten different and unrelated individuals and six different rodent cell lines. The genetic relationship of GUS to 28 enzyme markers representing 19 linkage groups was determined, and chromosome studies on selected cell hybrids were performed. The evidence indicates that the beta-glucuronidase gene is assigned to chromosome 7 in man. Comparative linkage data in man and mouse indicate that the structural gene GUS is located in a region on chromosome 7 that has remained conserved during evolution. Involvement of other chromosomes whose genes may be important in the final expression of GUS was not observed. A tetrameric structure of human beta-glucuronidase was demonstrated by the formation of three heteropolymers migrating between the human and mouse molecular forms in chromosome 7 positive cell hybrids. Linkage of GUS to other lysosomal enzyme genes was investigated. beta-Hexosaminidase (HEXB) was assigned to chromosome 5; acid phosphatase2 (ACP2) and esterase A4 (ES-A4) were assigned to chromosome 11; HEXA was not linked to GUS; and alpha-galactosidase (alpha-GAL) was localized on the X chromosome. These assignments are consistent with previous reports. Evidence was not obtained for a cluster of lysosomal enzyme structural genes. In demonstrating that GUS was not assigned to chromosome 9 utilizing an X/9 translocation segregating in cell hybrids, the gene coding for human adenylate kinase1 was confirmed to be located on chromosome 9.

Adenylate Kinase↗

PubMed1977

A family with syndactyly type II (synpolydactyly).

Syndactyly Type II is reported in eight members of a family in four generations. Affected individuals show two distinctive patterns of variation in the expression of the gene. Distortion of dermatoglyphic patterns is associated with the severe but not the mild manifestation of the malformation. The diagnostic significance of minimal features of the condition is discussed. Linkage data suggest that loci for Syndactyly II and for blood-group antigens ABO, MNSs, P, Rh and Kell are not closely linked.

Adult↗

PubMed1986

Structure of a class I gene from Syrian hamster.

Syrian hamsters possess a multigene class I family yet fail to perform several associative immunologic functions. In an attempt to determine whether representative hamster genes are structurally functional, we have cloned two closely linked class I-like genes and determined the complete sequence of the 5' member. Its exon organization is similar to that seen in mouse and man, although only two intracytoplasmic domains are encoded instead of the usual three. Comparison of the predicted amino acid sequence and the 3' untranslated region to mouse and human genes suggest along with the linkage data that the hamster gene may be related to either or both K and Qa region genes but probably not to D and L region genes.

Amino Acid Sequence↗

PubMed1987

Linkage relationships between X-linked retinitis pigmentosa and nine short-arm markers: exclusion of the disease locus from Xp21 and localization to between DXS7 and DXS14.

Linkage data between X-linked retinitis pigmentosa (XLRP) and nine X-chromosomal markers are reported. To test the assignment of XLRP to the Xp21 region (as considered at Human Gene Mapping 8), an analysis of XLRP and six markers flanking this region was undertaken. The XLRP locus was found to be excluded from the chromosome distal to ornithine transcarbamylase (OTC) (P = 6.5 X 10(-5]. Further data were accumulated with three more probes proximal to DXS7 (L1.28), the closest linked probe. Multipoint analysis of these data suggests a posterior probability of .94 that XLRP is proximal to DXS7 (L1.28), which has been mapped to the region Xp11.3.

Chromosome Mapping↗

PubMed1980

Probable linkage between the human galactose-1-P uridyl transferase locus and 9qh.

Evaluation of a family in which electrophoretic variants of the eznyme galactose-1-phosphate uridyl transferase (GALT) and 9qh variants occur demonstrates close linkage between these two traits: lod score of 3.67 at theta = 0. Taken with information indicating GALT is on the short arm of chromosome 9, these linkage data suggest that this locus is close to the centromere on the short arm of chromosome 9.

Blood Protein Electrophoresis↗