Genetic heterogeneity of autosomal dominant polycystic kidney disease in Argentina.

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited disorder with genetic heterogeneity. Up to three loci are involved in this disease, PKD1 on chromosome 16p13.3, PKD2 on 4q21, and a third locus of unknown location. Here we report the existence of locus heterogeneity for this disease in the Argentinian population by performing linkage analysis on 12 families of Caucasian origin. Eleven families showed linkage to PKD 1 and one family showed linkage to PKD2. Two recombinants in the latter family placed the locus PKD2 proximal to D4S1563, in agreement with data recently published on the cloning of this gene. Analysis of clinical data suggests a milder ADPKD phenotype for the PKD2 family.     

Estimating locus heterogeneity in autosomal dominant polycystic kidney disease (ADPKD) in the Spanish population.

Although most mutations causing ADPKD in European populations have been mapped to the PKD1 locus on chromosome 16, some of them appear to be unlinked to this locus. To evaluate the incidence of unlinked mutations in Spain we have typed 31 Spanish families from different geographical sites for six closely linked DNA polymorphic marker loci flanking PKD1 detected by probes D16S85, D16S21, D16S259, D16S125, D16S246, and D16S80. Multilocus linkage analysis indicated that in 26 families the disease resulted from PKD1 mutations, whereas in three families it resulted from mutations in a locus other than PKD1. The two other families were not informative. Using the HOMOG test, the incidence of the PKD1 linked mutations in Spain is 85%. Multipoint linkage analysis in the 26 PKD1 families showed that the disease locus lies in the interval between D16S259(pGGG1) and D16S125(26.6).     

Genetic heterogeneity in Korean families with autosomal-dominant polycystic kidney disease (ADPKD): the first Asian report

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease in adults, and the prevalence of this disease within the chronic haemodialysis patient population is known to be approximately 2% in Korea. So far, three genetic locus have been identified as being responsible for ADPKD, and approximately 85% of the cases in Western countries are related to the PKD1 gene. However, little information is available concerning the pattern of linkage analysis in Asian populations. METHODS: 48 families with hereditary renal cysts were recruited by consent and their molecular genetic characteristics were studied. Linkage analysis was done with microsatellite markers (PKD1: SM7, UT581, AC2.5, KG8, D16S418; PKD2: D4S423, D4S1534, D4S1542, D4S1544, D4S2460). Genomic DNA polymerase chain reaction (PCR) and polyacrylamide gel electrophoresis (PAGE) gel run were performed, and the resultant allele patterns were compared with sonographic findings. RESULTS: The results of this study showed that the ratio PKD1:PKD2 was 31:8, and that the PKD2 families exhibited a tendency toward a milder renal prognosis than the PKD1 families. CONCLUSION: We confirmed the applicability of linkage analysis for ADPKD in the Korean population, and our data confirmed a similar incidence of PKD1 (79%) and PKD2 (21%) in Korean patients as in the Western population.     

Genetic linkage study of familial Mediterranean fever (FMF) to 16p13.3 and evidence for genetic heterogeneity in the Turkish population.

Familial Mediterranean fever (FMF) is an autosomal recessive condition that is almost entirely restricted to the non-Askhenazi Jews, Arabs, Armenians, and Turks. Genetic linkage study of a large group of non-Turkish families has previously mapped the FMF locus to the 16p13.3 region and shown that this locus resides 0.305 cM distal to D16S246. Furthermore, allelic association has also been shown with D16S3070 (75%) and D16S3275 (66%). However, no genetic heterogeneity has been described for any of the three major reported groups of FMF families. Here, we describe the genetic linkage relationship of the fourth major group of Turkish families and report the first evidence for genetic heterogeneity of this condition. Two point linkage analysis and haplotype inspection of 15 DNA markers from the reported region of the FMF locus identified tight linkage in a group of six Turkish FMF families. A maximum lod score of 9.115 at theta = 0.00 was observed for D16S3024. Nine other DNA markers provided similar evidence of linkage with lod score values of above 5.21. However, two other FMF families were completely unlinked to this region of chromosome 16. Haplotype construction of DNA markers in five consanguineous linked families showed that a segment of homozygosity has been conserved for D16S3070 and D16S2617. No other DNA markers showed any such conservation. Therefore, we suggested that these two markers reside in close proximity to the FMF locus. Furthermore, we observed 80% allelic association with D16S2617 but no association with D16S3070 or any other DNA markers from the FMF critical region. In summary, we conclude that our Turkish families are also linked to the reported FMF locus at 16p13.3, there is a genetic heterogeneity for this condition at least in our group of Turkish families, and D16S2617 is in linkage disequilibrium in the Turkish FMF families. Combination of this study with previously published observations suggests that the FMF locus resides between D16S246 and D16S3070/D16S2617 and within a region of about 250-300 kb.     

DNA microsatellite analysis of families with autosomal dominant polycystic kidney disease types 1 and 2: evaluation of clinical heterogeneity between both forms of the disease.

We studied 17 large families affected by adult dominant polycystic kidney disease (ADPKD). Ultrasonographic analysis was performed on all the family members. DNA microsatellite markers closely linked to PKD1 on 16p13.3 were analysed, and linkage of the disease to this locus was determined. Families showing a negative linkage value were evaluated for linkage to the PKD2 locus on 4q. Five of the 17 families showed negative linkage for the 16p13.3 markers. In these families significant linkage to 4q was obtained. Renal cysts developed at an earlier age in PKD1 mutation carriers, and end stage renal failure occurred at an older age in people affected with PKD2. Analysis of large families with ADPKD in a Spanish population indicates that this is a genetically heterogeneous disorder, but mutations at only two loci are responsible for the development of the disease in most if not all the families. Clinicopathological differences between both forms of the disease occur, with subjects with ADPKD2 having a better prognosis than those with mutations at PKD1.     

Genetic linkage for Darier disease (keratosis follicularis)

Darier disease is an autosomal dominant skin disorder characterized by abnormal keratinocyte adhesion. Recent data have provided evidence for linkage of the Darier disease locus to 12q23–24.1 in British families. We have carried out linkage analysis using the 12q markers D12S58, D12S84, D12S79, D12S86, PLA2, and D12S63 in 6 Canadian families. Pairwise linkage analysis generated positive lod scores at all 6 markers at various recombination fractions, and each family showed positive lod scores with more than one marker. The peak lod score in the multipoint analysis (Z_max) was 5.5 in the interval between markers D12S58 and D12S84. These positive lod scores in North American families of varied European ancestry confirm the location of the Darier disease gene, and suggest genetic homogeneity. The future identification and sequencing of the gene responsible for Darier disease should lead to improved understanding of the disease and of keratinocyte adhesion in general. © 1995 Wiley-Liss, Inc.     

A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disease. Most families show positive linkage to polymorphic markers around the PKD1 (16p13.3) or PKD2 (4q21-23) loci. The PKD1 and PKD2 genes have been cloned and mutations defined in a number of patients. Several clinical studies have described a milder phenotype for PKD2 patients. More recently, evidence for a third genetic locus has been found in one Portuguese, one French-Canadian, and one Italian family. We identified a Spanish family with negative linkage to the PKD1 and the PKD2 loci. This family showed a very mild clinical phenotype compared to the other forms of ADPKD, including the non-PKD1/non-PKD2 families previously described.     

Mapping of the familial Mediterranean fever gene to chromosome 16.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurrent attacks of fever, synovitis, peritonitis, or pleurisy. Some patients eventually develop systemic amyloidosis. The biochemical cause of the disease is unknown. We have conducted a genome-wide search for the FMF locus using 125 different DNA markers and mapped the FMF gene to the short arm of chromosome 16. The study was performed on 35 Israeli families primarily of North African and Iraqi origin. For the five markers D16S82 (p41-1 Sacl), D16S80 (24-1 Taq1), D16S84 (pCMM65 Taq1), D16S83 (pEKMDA2-1 Rsal), and HBA (5'HVR Rsal) we obtained maximum lod scores of 2.72 (theta = 0.08), 10.34 (theta = 0.04), 9.66 (theta = 0.050, 9.35 (theta = 0.03), and 14.31 (theta = 0.08), respectively. Multipoint analysis with HBA and D16S84 defined as a fixed loci gave a maximum lod score of 19.86 centromeric to D16S84. Crossovers defined by these markers place the FMF gene in an area of approximately 5 cM between D16S80 and D16S84. Other genes mapped to this area (16p13.3) include phosphodiesterase IB (PDE1B), hydroxyacyl-glutathione hydrolase (HAGH), phosphoglycolate phosphatase (PGP), and the gene that causes adult polycystic kidney disease (PKD1). None of these genes bear an obvious pathophysiological relationship to FMF. Using additional markers from this region we hope to localize more precisely the FMF gene and to offer the possibility of prenatal diagnosis in selected cases. Our ultimate goal is to isolate and characterize the FMF gene.     

A closely linked DNA marker for facioscapulohumeral disease on chromosome 4q.

Close linkage of a hypervariable DNA probe on chromosome 4q (pH30, locus D4S139) has been found with the locus for facioscapulohumeral disease. Three recombinants were identified in a total of 140 meioses, giving a maximum lod score of 36.77 at a recombination fraction of 0.02. All but two of the families studied proved informative with this probe; all informative families showed evidence of linkage (except one family with a single scorable meiosis), making genetic heterogeneity unlikely from our data. The close linkage and highly informative nature of the probe will make it suitable for clinical application in presymptomatic and prenatal diagnosis. We have also confirmed loose linkage with the marker (Mfd22, locus D4S171) used to establish the initial assignment of the disorder to chromosome 4.     

Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16.

BACKGROUND. Familial Mediterranean fever is an autosomal-recessive disease characterized by acute attacks of fever with sterile peritonitis, pleurisy, or synovitis. The biochemical basis of the disease is unknown, but determining the chromosomal location of the gene for the disorder should be a first step toward defining the biochemical events. METHODS AND RESULTS. As part of a systematic genome-wide search, we sought evidence of linkage between familial Mediterranean fever and chromosome 16 DNA markers in 27 affected non-Ashkenazi Jewish families from Israel. Two loci from the subtelomeric region of the short arm of chromosome 16 (16p) had lod scores sufficient to establish linkage (a score greater than or equal to 3). One DNA marker (D16S84) gave a maximal lod score of 9.17 (odds of 10(9.17) to 1 in favor of linkage) at a recombination frequency (theta) of 0.04. A probe associated with the hemoglobin alpha complex (5'HVR) gave a maximal lod score of 14.47 at a theta of 0.06. Multipoint linkage analysis indicated that the following was the most likely gene order: the centromere, the gene for familial Mediterranean fever, D16S84, hemoglobin alpha, and the telomere. The maximal multipoint lod score was 19.86. There was a striking degree of homozygosity at chromosome 16p loci in the affected offspring of eight consanguineous couples. CONCLUSIONS. The gene that causes familial Mediterranean fever in non-Ashkenazi Jews maps to the short arm of chromosome 16.     

Map of 16 polymorphic loci on the short arm of chromosome 16 close to the polycystic kidney disease gene (PKD1).

To define the PKD1 locus further, the gene involved in the most frequent form of adult polycystic kidney disease, probes from 16 polymorphic loci were mapped on 16p13.1-pter with the combined use of cell lines containing rearranged chromosomes and family studies. Five breakpoints in the distal part of 16p arbitrarily subdivided the loci into five groups. By analysing 58 recombination events among 259 informative meioses in 12 large families with PKD, we were able to construct a linkage map for the distal part of 16p. The order of the markers obtained with chromosomal rearrangements was confirmed by the family studies. The D16S85 locus near alpha globin, D16S21, and D16S83 map distal, or telomeric, to PKD1. The polymorphic red cell enzyme phosphoglycolate phosphatase (PGP), D16S84, D16S259, and D16S246 showed no recombination with PKD1. The remaining nine RFLPs all map proximal to the PKD1 gene. By cosmid walking, additional RFLPs were detected at the D16S21 locus. A single intrahaplotype recombination observed defines the orientation of D16S21 relative to PKD1. The new polymorphisms are valuable for presymptomatic and prenatal diagnosis of PKD1. Furthermore, our map is both a good starting point for the physical map of 16p and a useful tool for the isolation of the PKD1 gene.     

A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q

To identify chromosomal regions containing susceptibility loci for systemic lupus erythematosus (SLE), we performed genome scans in families with multiple SLE patients from Iceland, a geographical and genetic isolate, and from Sweden. A number of chromosomal regions showed maximum lod scores (Z) indicating possible linkage to SLE in both the Icelandic and Swedish families. In the Icelandic families, five regions showed lod scores greater than 2.0, three of which (4p15-13, Z=3.20; 9p22, Z=2.27; 19q13, Z=2.06) are homologous to the murine regions containing the lmb2, sle2 and sle3 loci, respectively. The fourth region is located on 19p13 (D19S247, Z=2.58) and the fifth on 2q37 (D2S125, Z=2.06). Only two regions showed lod scores above 2.0 in the Swedish families: on chromosome 2q11 (D2S436, Z=2. 13) and 2q37 (D2S125, Z=2.18). The combination of both family sets gave a highly significant lod score at D2S125 of Z=4.24 in favor of linkage for 2q37. This region represents a new locus for SLE. Our results underscore the importance of studying well-defined populations for genetic analysis of complex diseases such as SLE.     

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci

Epidemiological and genetic linkage studies have indicated a strong genetic basis for development of inflammatory bowel disease (IBD) which was recently supported by discovery of the Crohn's disease (CD) susceptibility gene termed NOD2/CARD15. We carried out a genome-wide linkage study in Finnish IBD families, providing a particular advantage to map susceptibility genes for ulcerative colitis (UC) within a genetic isolate. Initially, 92 IBD families with 138 affected sib-pairs (ASPs), were genotyped for 429 markers spaced at approximately 10 cM intervals. Next, the loci on chromosomes 2p13-11, 11p12-q13, and 12p13-12 were high-density mapped in the extended family cohort of 130 families with 173 ASPs. In this study, the most significant lod scores were observed for the UC families on chromosome 2p11 (D2S2333), in the vicinity of the REG gene cluster which is strikingly overexpressed in the IBD mucosa. The maximum two-point lod score was 3.34 (dominant model), and the corresponding NPL score 2.61. For UC, the second highest two-point NPL score of 2.00 was observed at proximal 12p13, where also some evidence for linkage disequilibrium emerged (P=0.07 and P=0.007 for the basic and extended IBD cohorts, respectively). The highest two-point NPL score for the CD families was 2.34 at D12S78 (12q23) with significant evidence for linkage disequilibrium (P=0.004), and for the mixed (MX) families 2.07 at D4S406 near the linkage peak reported previously. This study confirmed several of the IBD loci that have previously been reported and gives evidence for new IBD loci on chromosomes 2p11, 11p12-q13, 12p13-12, 12q23, and 19q13.     

Genetic linkage between Huntington''s disease and D4S10(G8) in Scottish families

Genetic linkage between Huntington's disease (HD) and polymorphic DNA markers at the D4S10 locus has been investigated in 16 Scottish families. A maximum lod score of 3.499 at a recombination fraction of 0.07 was found, with 95% confidence limits of 0.02 and 0.22. Only one obvious recombinant was detected, and the wide confidence limits probably reflect the large number of unaffected individuals whose risk could only be estimated empirically.     

Presymptomatic molecular diagnosis of autosomal dominant polycystic kidney disease using PKD1-and PKD2-linked markers in Cypriot families

Autosomal dominant polycystic kidney disease (ADPKD), is a heterogeneous disorder, primarily characterized by the formation of cysts in the kidneys, and the late development in life of progressive chronic kidney failure. Three genes are implicated in causing ADPKD. One on chromosome 16, PKD1, accounts for 85–90% of all cases, and the PKD2 gene on chromosome 4 accounts for the remainder. A very rare third locus is still of unknown location. We used PKD1-and PKD2-linked polymorphic markers to make the diagnosis of ADPKD in young presymptomatic members in affected families. We showed that in young members of families where clinical diagnosis cannot be definitively established, molecular linkage analysis can assist clinicians in the diagnosis. In one family a 24-year old had one cyst on the right kidney; however, molecular analysis showed clearly that he had inherited the normal haplotype. In another family, in one part of the pedigree there was co-inheritance of the disease with a PKD1-linked haplotype which originated in a non-affected 78-year-old father. Analysis with PKD2-linked markers excluded this locus. The data can be explained in one of two ways. Either this family phenotype is linked to a third locus, or the proband was the first affected person, most probably because of a novel mutation in one of her father's chromosomes. In conclusion, the combined use of markers around the PKD1 and the PKD2 locus provides more definitive answers in cases where presymptomatic diagnosis is requested by concerned families.     

Evidence of a locus for schizophrenia and related disorders on the short arm of chromosome 5 in a large pedigree

We attempted to identify a locus for schizophrenia and related disorders in 24 nuclear families of schizophrenic probands using a predefined classification system for affected cases that included those disorders most clearly identified as sharing a genetic relationship with schizophrenia—schizoaffective disorder and schizotypal personality disorder. Initially, we evaluated 8 markers on chromosome 5 on the first 12 families with available genotyping and diagnostic assessments and, assuming autosomal dominant transmission, found a lod score of 2.67 for the D5S111 locus (5p14.1-13.1) in one large nuclear family (no. 17; sibship: n = 12; schizophrenia: n = 3; schizotypal personality disorder: n = 2); the other 11 families were much smaller, less complete, and provided little additional information. Other branches of no. 17 were then assessed and the 2-point lod score for family 17 rose to 3.72; using multipoint analysis the lod score in 17 was 4.37. When only schizophrenia was used to define affectedness, the positive evidence for linkage to D5S111 was greatly reduced. Sensitivity analysis indicated that the lod score is heavily dependent upon the predefined diagnostic criteria. Our studies of other families of schizophrenic probands eventually totalled 23, but linkage to D5S111 in these yielded a −2.41 lod score. The results provide evidence for genetic linkage of the D5S111 locus to schizophrenia and related disorders in one family. It may be of interest that over several generations, almost all the ancestors of family 17 could be traced back to a small, relatively isolated, hill region of Puerto Rico. © 1996 Wiley-Liss, Inc.     

Recombination or heterogeneity: is there a second locus for adult polycystic kidney disease?

Twenty-four families with adult onset polycystic kidney disease were typed for markers flanking the PKD1 locus on chromosome 16. The aggregated results gave a significant lod score in favour of linkage to PKD1. Within this group of families two showed unusual features: recombinations, including double recombinations, and, in one family, an unexpectedly high proportion of affected people. We consider the evidence that in these families the disease might result from a mutation at a different locus, PKD2, not linked to PKD1. We suggest that a useful test is to compare the relative numbers of meioses apparently non-recombinant and doubly recombinant for markers flanking the normal disease locus, ignoring meioses recombinant for only a single marker. Using this test, neither our two families nor the data published so far on other families provide compelling evidence for the existence of a second locus for adult polycystic kidney disease. For genetic counselling in families too small to give internal evidence for or against linkage, the extra uncertainty can be handled by using a higher recombination rate.     

Linkage and association studies with C8A and C8B RFLPs on chromosome 1

Linkage relations for the C8A and C8B Bam HI RFLPs have been investigated. A peak lod score of 4·52 at recombination fraction zero was obtained between the two C8 genes. Combined with our previously obtained linkage data (Rogde et al. 1986) the maximum lod score is 7·53 at recombination fraction zero. The compiled C8-PGM1 linkage data from this and the previous study gave a maximum lod score of 22·02 at recombination fraction 0·11 (0·07–0·16) with no sex difference. A chromosome 1p reference marker, D1S57 , has been applied in this linkage study. A maximum lod score of 5·06 between the C8 cluster and D1S57 at θ= 0·18 (0·11–0·28) was recorded. The linkage analyses and triply informative families gave evidence that the C8 loci are situated about halfway between PGM1 and D1S57 on the short arm of chromosome 1. There was no evidence of allelic association between the C8A and C8B Bam HI RFLPs in 62 unrelated haplotypes.     

Linkage between severe atopy and chromosome 11q13 in Japanese families

Atopy, characterised by allergic asthma and rhinitis, is due to increased IgE responses to common aeroallergens. An Oxford group has described maternal inheritance of atopy, where there is significant linkage between IgE responsiveness and a VNTR marker D11S97 and a CA microsatellite within a candidate gene, the high affinity IgE receptor β subunit(FcεRIβ), on chromosome 11q. Attempts at independent replication have produced conflicting results. We therefore recruited 270 atopic asthmatic probands in a Japanese community population for genetic linkage analysis. Four families, each with more than 15 meioses and a clear phenotype for atopy, were selected for genetic analysis. Atopy was defined as presence of all of raised total IgE, positive RAST and skin tests to three or more aeroallergens; non-atopy, as absence of all these criteria. Linkage analysis showed a maximum two-point lod score of 9.35 for D11S97 and FcεRIβ under the assumption of unequal rates of maternal and paternal recombination. Two families showed close genetic linkage with FcεRIβ with a pattern of maternal inheritance. These results from a Japanese population provide further evidence for genetic linkage between severe atopy and chromosome 11q13 and the likelihood of genomic imprinting at the locus.     

Genetic linkage mapping for a susceptibility locus to bipolar illness: Chromosomes 2,3,4,7,9,10p,11p,22, and Xpter

We are conducting a genome search for a predisposing locus to bipolar (manicdepressive) illness by genotyping 21 moderate-sized pedigrees. We report linkage data derived from screening marker loci on chromosomes 2, 3, 4, 7, 9, 10p, 11p, 22, and the pseudoautosomal region at Xpter. To analyze for linkage, two-point marker to illness lod scores were calculated under a dominant model with either 85% or 50% maximum penetrance and a recessive model with 85% maximum penetrance, and two affection status models. Under the dominant high penetrance model the cumulative lod scores in the pedigree series were less than ?2 at Θ = 0.01 in 134 of 142 loci examined, indicating that if the disease is genetically homogeneous linkage could be excluded in these marker regions. Similar results were obtained using the other genetic models. Heterogeneity analysis was conducted when indicated, but no evidence for linkage was found. In the course of mapping we found a positive total lod score greater than +3 at the D7S78 locus at Θ = 0.01 under a dominant, 50% penetrance model. The lod scores for additional markers within the D7S78 region failed to support the initial finding, implying that this was a spurious positive. Analysis with affected pedigree member method for COL1A2 and D7S78 showed no significance for linkage but for PLANH1, at the weighting functions f(p) = 1 and f(p) = 1/sqrt(p) borderline P values of 0.036 and 0.047 were obtained. We also detected new polymorphisms at the mineralocorticoid receptor (MLR) and calmodulin II (CALMII) genes. These genes were genetically mapped and under affection status model 2 and a dominant, high penetrance mode of transmission the lod scores of < ?2 at Θ = 0.01 were found. © 1994 Wiley-Liss, Inc.