Linkage data for Marfan syndrome and markers on chromosomes 1 and 11.

Six large families with classical Marfan syndrome were studied using markers on chromosomes 1 and 11. Two of three families tested showed negative scores using D1S7 but a third family gave a positive score (0.92) at theta = 0.1. The other chromosome 1 markers typed (MUCI, NGFB, D1S8) excluded close linkage. Negative lod scores with two chromosome 11q22 markers (D11S84, D11S148) excluded at least 20 cM in this area (Z = less than -2), which was chosen for study as two enzymes responsible for collagen degradation (collagenase and stromelysin) are localised to this region.     

Confirmation of genetic linkage between atopic IgE responses and chromosome 11q13.

Genetic linkage between atopic IgE responses and chromosome 11q13 (D11S97) has been previously reported in a limited number of extended families. Difficulties of phenotyping in the older family members, poor family structure in some families, and genetic heterogeneity were proposed as possible explanations for the variability in lod scores. To test this finding a second linkage study of 64 young nuclear families was undertaken and gave a two point lod score of 3.8 at theta = 0.07 (assuming theta m = theta f). A test of genetic heterogeneity in the nuclear families shows that atopic IgE responses are linked to this locus in 60 to 100% of families (approximate 95% confidence limits).     

Linkage analysis of neurofibromatosis (von Recklinghausen disease).

Linkage analysis of 28 genetic markers was undertaken in 108 subjects from 11 families with well-documented, classic, peripheral neurofibromatosis. Fifty-four persons were affected in one four-generation family, seven three-generation families, and three two-generation families. Lod scores were calculated using the standard LIPED programme for 49 combinations of theta male and theta female from 0.01 to 0.50. Lod scores excluded close linkage with 16 markers, including most tested on chromosome 1 and HLA on chromosome 6, and were inconclusive for 12 markers, including the secretor locus, closely linked to myotonic dystrophy. Analysis of five informative families resulted in a lod score of +2.2 for close linkage with GC on chromosome 4. However, the lod score for GC in the one additional informative family was negative, so that the final interpolated maximum was Z = 0.89 for theta male = 0.03, theta female = 0.28. Further studies are needed to evaluate this suggestion of linkage and possible genetic heterogeneity.     

Genetic linkage to the type VII collagen gene (COL7A1) in 26 families with generalised recessive dystrophic epidermolysis bullosa and anchoring fibril abnormalities.

To strengthen the evidence for genetic linkage to COL7A1, we have studied 26 generalised recessive dystrophic epidermolysis bullosa (EB) families of British, Italian, Irish, and South African origin. We chose two linkage markers, a COL7A1 PvuII intragenic polymorphism and a highly informative anonymous microsatellite marker, D3S1100, which maps close to the COL7A1 locus at 3p21.1-3. Diagnosis was established by family history, clinical examination, immunofluorescence, and ultrastructural studies. The PvuII marker was informative in 16 families with a maximum lod score (Zmax) of 3.51 at recombination fraction (theta) = 0. The D3S1100 microsatellite was informative in 24 out of 25 families with Zmax = 6.8 at theta = 0.05 (Z = 4.94 at theta = 0) and no obligatory recombination events. These data strongly suggest that COL7A1 mutations cause EB in these families and, combined with previous studies, indicate locus homogeneity. The importance of anchoring fibrils for dermal-epidermal adhesion is further underlined. D3S1100 may later prove useful in prenatal diagnosis of this disease, if used in combination with other markers.     

A ninth locus (RP18) for autosomal dominant retinitis pigmentosa maps in the pericentromeric region of chromosome 1

We studied a large Danish family of seven generations in which autosomal dominant retinitis pigmentosa (adRP), a heterogeneous genetic form of retinal dystrophy, was segregating. After linkage had been excluded to all known adRP loci on chromosomes 3q, 6p, 7p, 7q, 8q, 17p, 17q and 19q, a genome screening was performed. Positive lod scores suggestive of linkage with values ranging between Z = 1.58-5.36 at theta = 0.04-0.20 were obtained for eight loci on proximal 1p and 1q. Close linkage without recombination and a maximum lod score of 7.22 at theta = 0.00 was found between the adRP locus (RP18) in this family and D1S498 which is on 1q very near the centromere. Analysis of multiply informative meioses suggests that in this family D1S534 and D1S305 flank RP18 in interval 1p13-q23. No linkage has been found to loci from this chromosomal region in six other medium sized adRP families in which the disease locus has been excluded from all known chromosomal regions harbouring an adRP gene or locus suggesting that there is (at least) one further adRP locus to be mapped in the future.      

Evaluation of linkage of markers on chromosome 6p with schizophrenia in Taiwanese families

Previous studies have indicated possible linkage of schizophrenia with chromosome 6p21-24. In an attempt to replicate these findings, we studied the linkage of schizophrenia with nine markers on chromosome 6p21-24 in 39 Taiwanese schizophrenic nuclear families with at least two affected siblings. Two diagnostic models (narrow: Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia only; and broad: including schizophrenia, schizoaffective, and other nonaffective psychotic disorders) were used to define the disease phenotypes. With the broad and narrow diagnostic models, the marker D6S296 produced maximum two-point lod scores of 1.46 (straight theta = 0.2) and 1.35 (straight theta = 0. 2), respectively, in the recessive inheritance model. Assuming locus heterogeneity, a multipoint lod score of 0.85 was obtained between markers D6S296 and D6S277 under the narrow/recessive model. Maximum nonparametric lod scores of 1.25 ( p= 0.09) and 1.36 (p = 0.08) were observed, but still not statistically significant, at D6S296 in the narrow and broad diagnostic models, respectively. Both two-point analysis of the dominant model (lod score 0.85) and nonparametric analysis (lod score 1.25) showed a mild peak lod score appeared at marker D6S 285 as well. The results add some support to the suggestive linkage of schizophrenia with markers in the regions of chromosome 6p22 and 6p24 in an ethnically distinct Taiwanese sample. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:74-78, 2000.     

The hereditary pancreatitis gene maps to long arm of chromosome 7

Hereditary pancreatitis (HP) is an autosomal dominant disorder with incomplete penetrance characterized by recurring episodes of severe abdominal pain often presenting in childhood. Although this disorder has only been recently described, about 100 families have been documented worldwide. The pathophysiology of this disorder is unknown. Here, a large French family of 147 individuals (47 of whom were affected) from a four-generation kindred with HP has been examined and a genome segregation analysis of highly informative microsatellite markers has been performed. Linkage has been found between HP and six chromosome 7q markers. Maximal two point lod scores between HP and D7S 640, D7S 495, D7S 684, D7S 661, D7S 676 and D7S 688 were 4.00 (theta = 0.143), 5.85 (theta = 0.143), 4.91 (theta = 0.156), 8.58 (theta = 0.077), 8.28 (theta = 0.060), 4.40 (theta = 0.169), respectively. Multipoint linkage data combined with recombinant haplotype analysis indicated that the most likely order is: D7S 640-D7S 495-D7S 684-D7S 661-D7S 676-D7S 688, with the HP gene situated in the underlined region. As in all families reported in the literature, the clinical presentation of the disease is identical to the presentation of sporadic cases, one could expect that the knowledge of the HP gene could be a clue to pancreatitis in general. Based on its map position, this is the first step towards the positional cloning of the Hereditary Pancreatitis Gene (HPG).      

Presymptomatic diagnosis in Portuguese FAP families using intragenic RFLPs and (CA)n flanking markers by fluorescence based semiautomated DNA analysis.

Owing to the large size of the APC gene, responsible for familial adenomatous polyposis, direct screening for individual mutations is not a practical approach. In the present study we establish the methodology of fluorescence based semi-automated DNA analysis to perform presymptomatic diagnosis of members at risk from 11 Portuguese FAP families with three (CA)n markers flanking the APC gene, MBC, CB26, and YN5.64, and four intragenic RFLPs. Haplotypes were constructed on the basis of individual genotypes and their segregation through generations were followed. The study was informative for 12% of subjects using only intragenic RFLPs and increased to 90% when we used the three (CA)n flanking markers. We report two of the 11 families under study in our laboratory and show recombinant events leading to a precise localisation of the CB26 marker between D5S82 and the APC gene. In one family there was a loss of (CA) units of one allele of the CB26 marker from an unaffected mother to her son.     

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.     

Linkage analysis using multiple Xq DNA polymorphisms in normal families, families with the fragile X syndrome, and other families with X linked conditions.

Multipoint linkage analysis was undertaken with eight Xq cloned DNA sequences which identify one or more restriction fragment length polymorphisms in 26 families. These families comprise seven phase known normal families with three or more males in the third generation, seven families segregating for haemophilia B, one large family with dyskeratosis congenita, and 11 families with the fragile X syndrome. Phase known meioses informative for three or more loci supported the order centromere--DXYS1--DXS107--DXS102, DXS51--F9--FRAXA--DXS15, DXS52, F8--Xqter in each group of families studied. One of the normal families was segregating for protan colour blindness and showed a phase known recombination which would support the order centromere--F9--DXS52--CBP--Xqter. With the exception of DXYS1, all of these sequences have been localised to Xq27----qter by in situ hybridisation or hybridisation to Xq fragment panels, and on this basis should lie within 20 cM of one another. No recombination was observed between the sequences localised to Xq28, namely DXS52, F8, and DXS15 (between DXS15 and DXS52 Z = 12.25 at theta = 0 with confidence limits of 0 to 5 cM). However, an excess of recombination was apparent in the region of FRAXA with maximal lod scores as follows: F9 versus FRAXA (Z = 2.05, theta = 0.19), DXS52 versus FRAXA (Z = 1.85, theta = 0.26), and DXS15 versus FRAXA (Z = 1.33, theta = 0.27). No consistent differences were observed in the frequency of recombination when families with the fragile X syndrome were compared with normal families or families segregating for other X linked conditions. These results are compared with other published work and support the conclusion that although measurable linkage exists between these flanking markers and FRAXA, the intervals as measured by the frequency of meiotic recombination will seriously limit their clinical usefulness.     

Earliest description by Johann Friedrich Meckel,Senior (1750) of What is known today as Lutembacher syndrome (1916)

We initiated a genome-wide search for genes predisposing to schizophrenia by ascertaining 9 families, each containing three to five cases of schizophrenia. The 9 pedigrees were initially genotyped with 329 polymorphic DNA loci distributed throughout the genome. Assuming either autosomal dominant or recessive inheritance, 254 DNA loci yielded lod scores less than ?2.0 at θ = 0.0, 101 DNA markers gave lod scores less than ?2.0 at θ = 0.05, while 5 DNA loci produced maximum lod scores greater than 1: D4S35, D14S17, D15S1, D22S84, and D22S55. Of the DNA markers yielding lod scores greater than 1, D4S35 and D22S55 also were suggestive of linkage when the Affected-Pedigree-Member method was used. The families were then genotyped with four highly polymorphic simple sequence repeat markers; possible linkage diminished with DNA markers mapping nearby D4S35, while suggestive evidence of linkage remained with loci in the region of D22S55. Although follow-up investigation of these chromosomal regions may be warranted, our linkage results should be viewed as preliminary observations, as 35 unaffected persons are not past the age of risk. © 1994 Wiley-Liss, Inc.     

Genome scan for loci linked to mite sensitivity: the Collaborative Study on the Genetics of Asthma (CSGA)

Mite sensitivity has been reported to be a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome scan using mite reactivity (Dermatophagoides Pteronyssinus (Der p) and Dermatophagoides farinae (Der f)) as the phenotype was conducted. In 287 CSGA families, 122 were informative for linkage. Evidence supporting linkage was observed for regions on chromosome 19 (D19S591, lod=2.43, P=0.0008; D19S1037, lod=1.57, P=0.007) and chromosome 20 (D20S473/D20S604, lod=1.41, P=0.01). All three ethnic groups appeared to contribute to the evidence for linkage on chromosome 20. African-American families gave strongest support for linkage on chromosomes 3 (D3S2409, lod=1.33, P=0.01), 12 (D12S373, lod=1.51, P=0.008) and 18 (ATA82B02, lod=1.32, P=0.01). Caucasian families showed strong evidence for linkage on chromosome 19 (D19S591, lod=3.51, P=0.00006). Hispanic families supported linkage on chromosomes 11 (D11S1984, lod=1.56, P=0.007), 13 (D13S787, lod=1.30, P=0.01) and 20 (D20S470, lod=1.71, P=0.005). These results suggest that multiple genes may be involved in controlling skin reactivity to Dermatophoigoies.     

Autosomal dominant polycystic kidney disease: a linkage evaluation of heterogeneity in Italy. Italian Collaborative Group on Polycystic Kidney Disease

A survey of 29 families with Adult Polycystic Kidney Disease (ADPKD) was performed to evaluate the genetic heterogeneity of the disease in Italy. The approach was through the linkage between the disease and 2 polymorphic DNA fragments as detected by the probes 3'HVR and 24.1. Linkage between the polymorphic markers and the disease was confirmed, with the following lod scores: between 3'HVR and ADPKD1 = 12.974 at theta = 0.02; between 24.1 and ADPKD = 1.716 at theta = 0.07; between 3'HVR and 24.1 = 2.738 at theta = 0.09. No evidence of significant genetic heterogeneity in the examined Italian regions was detected.     

Two loci for Tuberous Sclerosis: one on 9q34 and one on 16p13

32 families informative for the segregation of Tuberous sclerosis (TSC) have been examined for genetic markers on chromosomes 9, 11, 12 and 16. In one large family there was clear evidence of linkage to markers on chromosome 16p13.3 (lodscore with D16S291 of 4·7 at θ= 0) but other families were too small to give individually convincing lodscores. Combined results for all families gave positive results with ABO/DBH on chromosome 9 (max lod 2·63) and with D16S291 on chromosome 16 (max lod 3·98) at values of theta of 0·2 in each case. Further analysis showed strong evidence for heterogeneity with approximately half the families linked to a locus TSC1 on chromosome 9 between ASS and D9S298 and half to TSC2 on chromosome 16 close to D16S291. There was no definite support for a third locus although in many families this could not be excluded. In three families the segregation pattern of TSC remains unexplained. In two of these the family apparently segregates for TSC1 but in each case a single affected individual appeared to exclude the whole of the candidate region. Preliminary analysis of clinical features did not reveal any definite differences in incidence of mental handicap between individuals in different linkage groups or with different sex of the parent of origin. The frequencies of periungual fibromas and facial angiofibromas were also similar in both linkage groups. The difficulties of detecting linkage in small families where there is locus heterogeneity are discussed. The program ZZ was found to be helpful in this respect.     

Prenatal diagnosis of Friedreich ataxia

Friedreich ataxia is a progressive neurodegenerative disorder affecting the peripheral and central nervous systems. One in 50,000 of the population are affected by this recessively inherited disorder, with onset usually before puberty. The recent localization of the disease locus to chromosome 9 has made it possible to provide genetic counselling to families with at least one affected child. Tight linkage of the disease mutation to an anonymous DNA marker MCT112 (D9S15) has been shown with a pairwise lod score of 36.1 at 0 = 0. We report here the first prenatal diagnosis in Friedreich ataxia. Using MCT112 and the confidence interval approach, we have calculated risks for a fully informative family with one affected sib.     

Emery-Dreifuss muscular dystrophy: localisation to Xq27.3----qter confirmed by linkage to the factor VIII gene.

Two families with Emery-Dreifuss muscular dystrophy (EMD) have been studied with DNA markers mapping to Xq27.3----qter. No recombination was observed in 11 phase known meioses informative for the factor VIII gene (F8C) and eight phase known meioses informative for DXS15 (DX13), giving maximum lod scores of 3.50 and 2.50 respectively at a recombination fraction of zero. DXS52 (St14) showed one recombinant in 12 phase known meioses giving a maximum lod score of 2.62 at a recombination fraction of 0.07. These results map EMD to the distal end of the long arm of the X chromosome and are an important step in the development of tests for carrier detection and prenatal diagnosis.     

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.     

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.     

Genomewide survey of panic disorder.

We completed a genome scan of 23 multiplex families of panic disorder. Ninety family members had DSM-III-R panic disorder, and another 23 had recurrent, spontaneous panic attacks that did not satisfy these criteria. We typed 469 markers from the CHLC map (ver 8c7) with an average intermarker distance of 10.3 cM. Two-point lod scores were calculated with both a dominant and a recessive model, and maps of lod scores < -2.00, assuming genetic homogeneity, were constructed by using DSM-III-R panic disorder as the affected phenotype. Lod scores were < -2.00 over 94-95% of the genome. The greatest lod score was 2.23 (theta = 0.15) at the D7S2846 locus, located at 57.8 cM on chromosome 7 according to the Marshfield Clinic map. Flanking markers analyzed in a nonparametric, multipoint analysis using GENEHUNTER resulted in an NPL score of 2.97 at 63 cM on the Marshfield map. This region lies within 15 cM from the D7S435 locus, where Knowles et al. [1998] obtained a lod score of 1.71 (theta = 0.10) for panic disorder (now 2.45 with the addition of new families; James Knowles, personal communication). Thus, the maximum evidence of linkage from two genome scans of panic disorder lies within a small region of chromosome 7p.     

Autosomal recessive retinitis pigmentosa locus RP28 maps between D2S1337 and D2S286 on chromosome 2p11-p15 in an Indian family

Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous disorders characterised by night blindness, constriction of visual field, and dystrophic changes of the retina. Previous genetic studies have shown extensive allelic and non-allelic genetic heterogeneity of RP. Here we describe an Indian family with multiple consanguineous marriages and a total of four patients with autosomal recessive (AR) RP. The homozygosity mapping strategy was successfully used and indicated close linkage between the disease locus and D2S380, D2S441, D2S291, and D2S1394 with maximum lod scores between 1.51-3.07 at theta=0.00. The analysis of multiply informative meioses maps the locus (RP28) for ARRP in this family between D1S1337 and D2S286 on 2p11-p15. The involvement of visinin (VSNL1), a promising candidate gene assigned to chromosome 2p by previous studies, has been excluded by the absence of linkage.