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。     

Localization of branchio-oto-renal (BOR) syndrome to a 3 Mb region of chromosome 8q

Branchio-oto-renal (BOR) syndrome is an autosomal dominant condition of branchial arch anomalies, deafness and renal dysplasia. Clinical manifestations tend to have considerable intrafamilial and interfamilial variability. Previous linkage studies had localized the gene responsible for BOR syndrome to a broad region of chromosome 8q. Using 10 microsatellite markers, we have further refined the localization of this disorder by establishing tight linkage to two markers, D8S279 and D8S530 (Z_max = 3.91 and Z_max = 2.83 respectively at Θ = 0.00. These markers are within 1 cM of one another. Multipoint analysis, involving 7 loci, placed the gene between these markers, with a lod-1 confidence interval 0.7 cM proximal to D8S530 and 0.6 cM distal to D8S279. © 1994 Wiley-Liss, Inc.     

Further refinement of Pendred syndrome locus by homozygosity analysis to a 0.8 cM interval flanked by D7S496 and D7S2425.

Pendred syndrome is an autosomal recessive disease characterised by congenital sensorineural deafness and goitre. The gene responsible for Pendred syndrome has been mapped to chromosome 7q31 in a 5.5 centimorgan (cM) interval flanked by D7S501 and D7S523. This interval was recently refined a to 1.7 cM interval located between D7S501 and D7S692. In the present study, we report linkage analysis data on a large consanguineous family genotyped with eight microsatellite markers located between D7S501 and D7S523. Complete cosegregation with the disease locus was observed with the loci analysed, which further supports locus homogeneity for Pendred syndrome and close linkage to this region. Haplotype analysis placed the Pendred syndrome gene between D7S496 and D7S2425 in a 0.8 cM interval. This additional refinement of the Pendred syndrome region will facilitate the construction of a physical map of the region and will help the identification of candidate genes.     

A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27.

Prevalence of coronary heart disease (CHD), of type 2 diabetes (T2DM) and of the metabolic syndrome are in Mauritius amongst the highest in the world. As T2DM and CHD are closely associated and have both a polygenic basis, we conducted a 10 cM genome scan with 403 microsatellite markers in 99 independent families of North-Eastern Indian origin including 535 individuals. Families were ascertained through a proband with CHD before 52 years of age and additional sibs with myocardial infarction (MI) or T2DM. Model-free two-point and multipoint linkage analysis were performed using the Mapmarker-Sibs (MLS) and maximum-likelihood-binomial (MLB) programs for autosomal markers and the Aspex program for chromosome X markers. In a second step, additional markers were studied to increase the genetic map density in three regions on chromosomes 3, 8 and 16 where initial indication for linkage was found. Our data show suggestive linkage with CHD on chromosome 16p13-pter with the MLS statistics at 8.69 cM (LOD = 3.06, P = 0.00017) which partially overlaps with a high pressure (HBP) peak. At the same locus, a nominal indication for linkage with T2DM was found in 35 large T2DM Pondicherian families also having Indian origin. With respect to region 8q23, we found suggestive linkage with T2DM (LOD = 2.55, P = 0.00058) as well as with HBP. On 3q27, we replicated previous indication for linkage found in Caucasians (for the metabolic syndrome and for diabetes) according to the categorized trait for CHD and MI with the MLB statistics (LOD = 2.13, P = 0.0009). The genome scan also revealed nominal evidence of linkage with CHD on 10q23 (LOD = 2.06, P = 0.00188). Interestingly, we detected in the same region overlapping linkages with three QTLs: age of onset of CHD (LOD = 2.03), HDL cholesterol (LOD = 1.48) and LDL/HDL ratio (LOD = 1.34). Ordered-subset analysis based on family body mass index ranking replicated finding on 2q37 for T2DM (at Calpain 10 locus). These results show the first evidence for susceptibility loci that predispose to CHD, T2DM and HBP in the context of the metabolic syndrome.     

Mapping of a novel type III variant of Knobloch syndrome (KNO3) to chromosome 17q11.2

Knobloch syndrome (KNO) is an autosomal recessive disorder characterized by ocular abnormalities (myopia and retinal detachment) and occipital encephalocele. The syndrome is clinically and genetically heterogeneous (KNO1, KNO2). Previously germline mutations in COL18A1 (21q22.3) were detected in some families, but in other kindreds linkage to COL18A1 was excluded. We ascertained a large consanguineous family with high myopia, vitreoretinal degeneration and occipital scalp defect with autosomal recessive mode of inheritance. Due to the overlapping clinical presentation of this family with Knobloch syndrome we propose this phenotype as a type III variant of KS (KNO3). A genome wide linkage study using microsatellite markers at 10-20 cM interval revealed linkage to 17q11.2 with a maximum LOD scores 3.40 (theta = 0.00) for markers D17S1307 and D17S1166. Fine mapping defined a 2.67 cM disease region between D17S1307 and D17S798. Mutation analysis of three candidate genes (UNC119, MYO1D, and RAB11FIP4) within the disease region did not identify any disease-associated mutation in affected individuals.     

Clouston hidrotic ectodermal dysplasia (HED): genetic homogeneity, presence of a founder effect in the French Canadian population and fine genetic mapping

HED is an autosomal dominant skin disorder that is particularly common in the French Canadian population of south-west Quebec. We previously mapped the HED gene to the pericentromeric region of chromosome 13q using linkage analysis in eight French Canadian families. In this study, we extend our genetic analysis to include a multiethnic group of 29 families with 10 polymorphic markers spanning 5.1 cM in the candidate region. Two-point linkage analysis strongly suggests absence of genetic heterogeneity in HED in four families of French, Spanish, African and Malaysian origins. Multipoint linkage analysis in all 29 families generated a peak lod score of 53.5 at D13S1835 with a 1 lod unit support interval spanning 1.8 cM. Recombination mapping placed the HED gene in a 2.4 cM region flanked by D13S1828 proximally and D13S1830 distally. We next show evidence for a strong founder effect in families of French Canadian origin thereby representing the first example of a founder disease in the south-west part of the province of Quebec. Significant association was found between HED in these families and all markers analysed (Fisher's exact test, P < 0.001). Complete allelic association was detected at D13S1828, D13S1827, D13S1835, D13S141 and D13S175 (P(excess) = 1) spanning 1.3 cM. A major haplotype including all 10 associated alleles was present on 65% of affected chromosomes. This haplotype most likely represents the founder haplotype that introduced the HED mutation into the French Canadian population. Luria-Delbrück equations and multipoint likelihood linkage disequilibrium analysis positioned the gene at the D13S1828 locus (likely range estimate: 1.75 cM) and 0.58 cM telomeric to this marker (support interval: 3.27 cM) respectively.     

Meta-analysis of genome-wide linkage studies for multiple sclerosis, using an extended GSMA method

Many genome-wide linkage studies in multiple sclerosis (MS) have been performed, but results are disappointing, with linkage confirmed only in the HLA region. We combined results from all available, non-overlapping genome-wide linkage studies in MS using the Genome Search Meta-Analysis method (GSMA). The GSMA is a rank-based analysis, which assesses the strongest evidence for linkage within bins of traditionally 30 cM width on the autosomes and X chromosome. Genome-wide evidence for linkage was confirmed on chromosome 6p (HLA region; P=0.00004). Suggestive evidence for linkage was found on chromosomes 10q (P=0.0077), 18p (P=0.0054) and 20p (P=0.0079). To explore how these results could be affected by bin definition, we analysed the data using different bin widths (20 and 40 cM) and using a shifted 30 cM bin by moving bin boundaries by 15 cM. Consistently significant results were obtained for the 6p region. The regions on 10q and 18p provided suggestive evidence for linkage in some analyses, and, interestingly, a region on 6q, that showed only nominal significance in the original analysis, yielded increased, suggestive significance in two of the additional analyses. These regions may provide targets to focus candidate gene studies or to prioritise results from genome-wide association studies.     

Genomewide linkage scan in a multigeneration Caucasian pedigree identifies a novel locus for keratoconus on chromosome 5q14.3-q21.1.

PURPOSE: Keratoconus is a corneal dystrophy with an incidence of 1 in 2000 and a leading cause for cornea transplantation in Western developed countries. Both clinical observations and segregation analyses suggest a major role for genes in its pathogenesis. It is genetically heterogeneous, most commonly sporadic, but inherited patterns with recessive or dominant modes have also been reported. We studied a four-generation autosomal-dominant pedigree to identify disease loci for keratoconus. METHODS: A two-stage genome-wide scan was applied to 27 family members. First linkage analysis was performed with 343 microsatellite markers along the 22 autosomal chromosomes at approximately 10 cM density. This was followed by fine mapping at approximately 2 cM density, in regions suggestive of linkage. Multipoint linkage analysis was performed using GeneHunter2. RESULTS: Evidence of suggestive linkage from the initial scan was observed at the 82 to 112 cM region of chromosome 5q14.1-q21.3 with a maximum lod score (LOD) of 3.48 (penetrance = 0.5). Fine mapping by testing an additional 11 microsatellite markers at 1 to 3 cM intervals revealed a narrower and higher peak (99-119 cM) with LOD 3.53. By analysis of the recombination of haplotypes, the putative locus of keratoconus was further narrowed to a 6 cM region (8.2 Mbp physical distance) between markers D5S2499 and D5S495. CONCLUSION: These results indicate a promising new locus for keratoconus in this pedigree. Because of the heterogeneous nature of keratoconus, this locus may be specific to familial autosomal-dominant keratoconus. Nevertheless, the identification of this locus may provide new insights into the pathogenesis of keratoconus.     

Linkage disequilibrium in inbred North African families allows fine genetic and physical mapping of triple A syndrome

Triple A syndrome (Allgrove syndrome, MIM No. 231550) is a rare autosomal recessive disorder characterised by ACTH-resistant adrenal insufficiency, achalasia of the cardia, and alacrimia. The triple A gene has been previously mapped to chromosome 12q13 in a maximum interval of 6 cM between loci D12S1629 and D12S312. Using linkage analysis in 12 triple A families, mostly originating from North Africa, we confirm that the disease locus maps to the 12q13 region (Zmax = 10.89 at theta = 0 for D12S1604) and suggest that triple A is a genetically homogeneous disorder. Recombination events as well as homozygosity for polymorphic markers enabled us to reduce the genetic interval to a 3.9 cM region. Moreover, total linkage disequilibrium was found at the D12S1604 locus between a rare allele and the mutant chromosomes in North African patients. Analysis of markers at five contiguous loci showed that most of the triple A chromosomes are derived from a single founder chromosome. As all markers are located in a 0 cM genetic interval and only allele 5 at the D12S1604 locus was conserved in mutant chromosomes, we speculate that the triple A mutation is due to an ancient Arabian founder effect that occurred before migration to North Africa. Since we also found linkage disequilibrium at D12S1604 in two patients from Southern Europe (France and Spain), the founder effect might well extend to other Mediterranean countries. Taking advantage of a YAC contig encompassing the triple A minimal physical region, the triple A gene was mapped to a 1.7 Mb DNA fragment accessible to gene cloning.     

Amish brittle hair syndrome gene maps to 7p14.1

The brittle hair syndrome (BHS) is characterized by short stature, intellectual impairment, brittle hair, and decreased fertility in 20 members from a large Amish consanguineous kindred previously reported affected with this syndrome. We mapped the BHS gene by genome scan to chromosome 7p14.1. Evidence of linkage was supported by a maximum multipoint LOD score of 6 obtained with GENEHUNTER for the linkage interval defined by markers D7S484-D7S2422 distant by 17.2 cM. Two-point linkage analysis performed with SUPERLINK yielded a LOD score of 9.02 at theta = 0 for marker D7S2497 located within that interval. Analysis of haplotypes homozygous-by-descent allowed fine mapping of the BHS gene within a 4.81 cM interval delimited by markers D7S2497 and D7S691, a region that spreads over 3.42 Mb.     

Fine mapping of the alpha-T catenin gene to a quantitative trait locus on chromosome 10 in late-onset Alzheimer's disease pedigrees

Using plasma amyloid beta protein (Abeta42) levels as an intermediate, quantitative phenotype for late onset Alzheimer's disease (LOAD), we previously obtained significant linkage at approximately 80 cM on chromosome 10. Linkage to the same region was obtained independently in a study of affected LOAD sib-pairs. Together, these two studies provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Abeta42. VR22 is a large (1.7 Mb) gene located at 80 cM that encodes alpha-T catenin, which is a binding partner of beta catenin. This makes VR22 an attractive candidate gene because beta catenin interacts with presenilin 1, which has many mutations that elevate Abeta42 and cause early onset familial AD. We identified two intronic VR22 SNPs (4360 and 4783) in strong linkage disequilibrium (LD) that showed highly significant association (P=0.0001 and 0.0006) with plasma Abeta42 in 10 extended LOAD families. This association clearly contributed to the linkage at approximately 80 cM because the lod scores decreased when linkage analysis was performed conditional upon the VR22 association. This association replicated in another independent set of 12 LOAD families (P=0.04 for 4783 and P=0.08 for 4360). Bounding of the association region using multiple SNPs showed VR22 to be the only confirmed gene within the region of association. These findings indicate that VR22 has variant(s) which influence Abeta42 and contribute to the previously reported linkage for plasma Abeta42 in LOAD families.     

Mapping of a Gene for Alopecia with Mental Retardation Syndrome (APMR3) on Chromosome 18q11.2-q12.2

Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder characterized by total or partial absence of hair from the scalp and other parts of the body and associated with mental retardation. Previously, we have reported the mapping of two alopecia and mental retardation genes ( APMR1 and APMR2 ) on human chromosome 3. In the present study, after excluding both of these loci through linkage analysis, a whole genome scan was performed by genotyping 396 polymorphic microsatellite markers located on 22 autosomes and the X and Y chromosomes. A disease locus was mapped to a 10.9 cM region, flanked by markers D18S866 and D18S811, on chromosome 18q11.2–q12.2. A maximum two-point LOD score of 3.03 at θ= 0.0 was obtained with marker D18S1102. Multipoint linkage analysis resulted in maximum LOD scores of 4.03 with several markers in the candidate region. According to the Rutgers combined linkage-physical map of the human genome (build 36) this region covers 12.17 Mb. DNA sequence analysis of nine candidate genes including DSC3 , DSC1 , DSG1 , DSG4 , DSG3 , ZNF397 , ZNF271 , ZNF24 and ZNF396 did not reveal any sequence variants in the affected individuals of the family presented here.     

Follow-up mapping supports the evidence for linkage in the candidate region at 9q22 in the NIMH Alzheimer's disease Genetics Initiative cohort.

Other than the APOE peak at 19q13, the 9q22 region was identified in our original genomic scan as the candidate region with the highest multipoint lod score (MLS) in the subset of late onset Alzheimer's Disease (AD) families (MLS = 2.9 at 101 cM) from the NIMH Genetics Initiative sample. We have now genotyped an additional 12 short tandem repeats (STR) in this region. Multipoint analysis shows the region remains significant with an increase in the peak MLS from 2.9 to 3.8 at 95 cM near marker D9S1815, and the 1 LOD interval narrows from 21.5 to 11 cM. HLOD scores also provide evidence for significant linkage (4.5 with an alpha = 31%) with a further narrowing of the region to 6.6 cM (92.2-98.8 cM). Single nucleotide polymorphisms (SNPs) in the Ubiquilin1 gene (UBQLN1), located at 83.3 cM, have been reported to be significantly associated to AD, accounting for a substantial portion of the original linkage signal [Bertram et al., 2005]. Our analyses of the higher resolution genotype data generated here provide further support for the existence of a least one additional locus on chromosome 9q22. In an effort to pinpoint this putative AD susceptibility gene, we have begun to analyze SNPs in other candidate genes in and around this narrowed region to test for additional associations to AD.     

Homozygosity mapping of lethal congenital contractural syndrome type 2 (LCCS2) to a 6 cM interval on chromosome 12q13

We have recently described a novel autosomal recessive disorder, lethal congenital contractural syndrome type 2 (LCCS2) (OMIM 607598), in a large Israeli Bedouin kindred. The phenotype, which is lethal in the neonatal period, is distinguished by the presence of a markedly distended urinary bladder. Association of LCCS2 to the known loci associated with arthogryposis was excluded. In the present study, we set out to determine the genetic locus harboring the gene defective in this disease. We performed genome-wide linkage analysis, demonstrating linkage to a approximately 6 cM (corresponding to approximately 7.2 Mb) homozygosity region on chromosome 12q13 between markers D12S1604 and D12S83. Based on recombination events, the interval harboring the disease-associated locus was further narrowed to a region spanning approximately 6 cM ( approximately 6.4 Mb) between D12S325 and D12S1072. Linkage of LCCS2 to that locus was established, with two significant maximum peaks at markers D12S1604 (Z(max) = 10.56 at theta = 0.01) and D12S1700 (Z(max) = 9.23 at theta = 0.00).     

Genetic mapping of vascular calcified plaque loci on chromosome 16p in European Americans from the diabetes heart study

A linkage peak for carotid artery calcified plaque (CarCP) on chromosome 16p (LOD 4.39 at 8.4 cM) in families with type 2 diabetes mellitus (T2DM) from the Diabetes Heart Study (DHS) has been refined. Fine mapping encompassed 104 single-nucleotide polymorphisms (SNPs) in 937 subjects from 315 families; including 45 SNPs in six candidate genes (CACNA1H, SEPX1, ABCA3, IL32, SOCS1, CLEC16A). Linkage and association analyses using variance components analysis adjusting for age, gender, body mass index (BMI), and diabetes status refined the CarCP linkage into two distinct peaks (LODs: 3.89 at 6.9 cM and 4.86 at 16.0 cM). Evidence of linkage for coronary calcified plaque (LOD: 2.27 at 19 cM) and a vascular calcification principle component (LOD: 3.71 at 16.0 cM) was also observed. The strongest evidence for association with CarCP was observed with SNPs in the A2BP1 gene region (rs4337300 P= 0.005) with modest evidence of association with SNPs in CACNA1H (P= 0.010-0.033). Bayesian quantitative trait nucleotide (BQTN) analysis identified a SNP, rs1358489, with either a functional effect on CarCP or in linkage disequilibrium (LD) with a functional SNP. This study refined the 16p region contributing to vascular calcification. The causal variants remain to be identified, but results are consistent with a linkage peak that is due to multiple common variants, though rare variants cannot be excluded.     

Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene. In an attempt to replicate this finding, we assessed linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Studies Program, included 392 sampled affected subjects and 216 affected sib pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizoaffective disorder, depressed. The families had mixed ethnic backgrounds. The majority were northern European-American families (n = 62, 37%), but a substantial proportion were African-American kindreds (n = 60, 36%). Chromosome 13 markers, spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the 13q32 region were genotyped and the data analyzed using semi-parametric affected only linkage analysis. For the combined sample (with race broadly defined and schizophrenia narrowly defined) the maximum LOD score was 1.43 (Z-score of 2.57; P = 0.01) at 79.0 cM between markers D13S1241 (76.3 cM) and D13S159 (79.5 cM). Both ethnic groups showed a peak in this region. The peak is within 3 cM of the peak reported by Brzustowicz et al. [1999: Am J Hum Genet 65:1096-1103].     

Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan

In a 12.5 cM genome-wide scan for psoriasis susceptibility loci, recombination-based tests revealed linkage to the HLA region (Zmax = 3.52), as well as suggestive linkage to two novel regions: chromosome 16q (60-83.1 cM from pter, Zmax = 2.50), and chromosome 20p (7.5-25 cM from pter, Zmax = 2.62). All three regions yielded P values < or = 0.01 by non-parametric analysis. Recombination-based and allele sharing methods also confirmed a previous report of a dominant susceptibility locus on distal chromosome 17q (108.2 cM from pter, Zmax = 2.09, GENEHUNTER P = 0.0056). We could not confirm a previously reported locus on distal chromosome 4q; however, a broad region of unclear significance was identified proximal to this proposed locus (153.6- 178.4 cM from pter, Zmax = 1.01). Taken together with our recent results demonstrating linkage to HLA-B and -C, this genome-wide scan identifies a psoriasis susceptibility locus at HLA, confirms linkage to 17q, and recommends two novel genomic regions for further scrutiny. One of these regions (16q) overlaps with a recently-identified susceptibility locus for Crohn's disease. Psoriasis is much more common in patients with Crohn's disease than in controls, suggesting that an immunomodulatory locus capable of influencing both diseases may reside in this region.      

Fine mapping of a schizophrenia susceptibility locus at chromosome 6q23: increased evidence for linkage and reduced linkage interval

We previously reported an autosomal scan for schizophrenia susceptibility loci in a systematically recruited sample of Arab Israeli families. The scan detected significant evidence for linkage at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P=0.000004) and a multipoint parametric LOD score of 4.16. In order to refine this finding we typed 42 additional microsatellite markers on chromosome 6q between D6S1570 (99.01 cM from the pter) and D6S281 (190.14 from the pter) in the same sample (average intermarker distance approximately 1.7 cM). In the 23 cM region between D6S1715 and D6S311, markers were more closely spaced ( approximately 1.1 cM). Multipoint nonparametric and parametric and single point linkage analyses were performed. The peak NPL rose to 4.98 (P=0.00000058) at D6S1626 (136.97 cM), immediately adjacent to D6S292 (NPL 4.98, P=0.00000068), the marker that gave the highest NPL in the original genome scan, under the broad diagnostic category. The putative susceptibility region (NPL-1) was reduced from 12.0 to 4.96 cM. The peak multipoint parametric LOD score was 4.63 at D6S1626 under a dominant genetic model, core diagnostic category and the LOD-1 interval was 2.10 cM. The maximum single point LOD score (3.55, theta=0.01) was also at D6S1626 (dominant model, core diagnostic category). Increased evidence for linkage in the same sample as in the original genome scan and consistent localization of the linkage peak add further support for the presence of a schizophrenia susceptibility locus at chromosome 6q23. Moreover, the markedly reduced linkage interval greatly improves prospects for identifying a schizophrenia susceptibility gene within the implicated region.     

Probable localisation of the Coffin-Lowry locus in Xp22.2-p22.1 by multipoint linkage analysis

The Coffin-Lowry syndrome (McKusick No. 30360) is a rare genetically transmitted disorder characterized by severe mental retardation, "coarse" facial appearance, thick soft skin, tapering fingers, and progressive skeletal abnormalities. X-linked inheritance is implied since the males are severely affected with variably mild manifestations in carrier women. We have performed a linkage analysis with many X-linked RFLP markers in 4 families. Positive two-point lod scores were obtained with DXS28 (z(theta) = 2.00 at theta = 0.05) and DXS41 (z(theta) = 1.26 at theta = 0.10). We performed a 5-point linkage analysis using the LINKMAP program assuming that DXS16 and DXS43 are a single locus and using the following fixed map (distances in centimorgans): DXS85 - 18cM - (DXS16, DXS43) - 13cM - DXS41 - 5cM -DXS28. This gave a multipoint lod score of 3.41 for a localisation in Xp22.2-p22.1, between DXS43 and DXS41.     

Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample.

Previous studies have reported genetic linkage evidence for a schizophrenia gene on chromosome 15q. Here, chromosome 15 was examined by genetic linkage analysis using 166 schizophrenia families, each with two or more affected subjects. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Study Program, consisted of 392 sampled affected subjects and 216 affected sibling pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizo-affective disorder, depressed. Participating families had diverse ethnic backgrounds. The largest single group were northern European American families (n = 62, 37%), but a substantial proportion was African American kindreds (n = 60, 36%). The chromosome 15 markers tested were spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the region surrounding the alpha-7 nicotinic cholinergic receptor subunit gene (CHRNA7). These markers were genotyped and the data analyzed using semiparametric affecteds-only linkage analysis. In the European American families, there was a maximum Z-score of 1.65 between markers D15S165 and D15S1010. These markers are within 1 cM from CHRNA-7, the site previously implicated in schizophrenia. However, there was no evidence for linkage to this region in the African America kindreds.