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1.
Vivek S Yellore Jeanette C Papp Eric Sobel M Ali Khan Sylvia A Rayner Debora B Farber Anthony J Aldave 《Genetics in medicine》2007,9(4):228-234
PURPOSE: The study purpose was to identify the genetic basis of posterior polymorphous corneal dystrophy, an autosomal dominant disorder of the corneal endothelium that is associated with the development of corneal edema, necessitating corneal transplantation for visual rehabilitation. Glaucoma also develops in up to 40% of patients with posterior polymorphous corneal dystrophy. METHODS: Linkage analysis, using microsatellite markers previously used to demonstrate linkage of posterior polymorphous corneal dystrophy to the chromosome 20 candidate region known as posterior polymorphous corneal dystrophy 1, was performed in 29 members of a family with posterior polymorphous corneal dystrophy. Thirty-four microsatellite markers were used to refine the posterior polymorphous corneal dystrophy 1 interval. TCF8, located on chromosome 10, was screened in an affected family member to exclude posterior polymorphous corneal dystrophy 3. RESULTS: Significant evidence of linkage to the posterior polymorphous corneal dystrophy 1 interval was obtained with both single-point and multipoint analyses. The largest single-point log odds ratio score obtained was 4.38 (theta=0) at marker D20S471; within 4.7 Mbp (7.2 cM) of D20S471 eight markers provided single-point log odds ratio scores of greater than 3.00 and three markers provided single-point log odds ratio scores greater than 4.00. The largest multipoint log odds ratio score obtained was 4.83, found across the adjacent markers D20S844, D20S191, D20S484, and D20S111. The support interval for posterior polymorphous corneal dystrophy 1 in the family we report is approximately 13.5 Mbp (10 cM) long and lies between the markers D20S182 and D20S195. Eleven markers have multipoint log odds ratio scores greater than 4.0 within this region. No coding region mutations were identified in TCF8 in an affected member of the family, effectively excluding posterior polymorphous corneal dystrophy 3. CONCLUSIONS: The originally described 19.8 cM posterior polymorphous corneal dystrophy 1 candidate disease interval has been refined to a 10 cM interval between markers D20S182 and D20S195. A portion of this refined interval overlaps a more recently reported posterior polymorphous corneal dystrophy 1 interval, with only 20 known and predicted genes mapped to the 2.4 cM common interval. 相似文献
2.
Kunka Kamenarova Sylvia Cherninkova Margarita Romero Durán DeQuincy Prescott Maria Lourdes Valdés Sánchez Vanio Mitev Ivo Kremensky Radka Kaneva Shomi S Bhattacharya Ivailo Tournev Christina Chakarova 《European journal of human genetics : EJHG》2013,21(3):338-342
Here we report recruitment of a three-generation Romani (Gypsy) family with autosomal dominant cone-rod dystrophy (adCORD). Involvement of known adCORD genes was excluded by microsatellite (STR) genotyping and linkage analysis. Subsequently, two independent total-genome scans using STR markers and single-nucleotide polymorphisms (SNPs) were performed. Haplotype analysis revealed a single 6.7-Mb novel locus between markers D10S1757 and D10S1782 linked to the disease phenotype on chromosome 10q26. Linkage analysis gave a maximum LOD score of 3.31 for five fully informative STR markers within the linked interval corresponding to the expected maximum in the family. Multipoint linkage analysis of SNP genotypes yielded a maximum parametric linkage score of 2.71 with markers located in the same chromosomal interval. There is no previously mapped CORD locus in this interval, and therefore the data reported here is novel and likely to identify a new gene that may eventually contribute to new knowledge on the pathogenesis of this condition. Sequencing of several candidate genes within the mapped interval led to negative findings in terms of the underlying molecular pathogenesis of the disease in the family. Analysis by comparative genomic hybridization excluded large chromosomal aberrations as causative of adCORD in the pedigree. 相似文献
3.
Linkage of posterior polymorphous corneal dystrophy to 20q11 总被引:5,自引:3,他引:2
Heon Elise; Mathers William D.; Alward L.M.Alward; Weisenthal Robert W.; Sunden Sara L.F.; Fishbaugh Jill A.; Taylor Chris M.; Krachmer Jay H.; Sheffield Val C.; Stone Edwin M. 《Human molecular genetics》1995,4(3):485-488
Posterior polymorphous dystrophy (PPMD) is an autosomal dominantdisorder of the cornea that is clinically recognized by thepresence of vesicles on the endothelial surface of the cornea.The corneal endothelium is normally a single layer of cellsthat lose their mitotic potential after development is complete.In PPMD, the endothelium is often multi-layered and has severalother characteristics of an epithelium including the presenceof desmosomes, tonofilaments, and microvilli. These abnormalcells retain their ability to divide and extend onto the trabecularmeshwork to cause glaucoma in up to 40% of cases. A large familywith 21 members affected with PPMD was genotyped with shorttandem repeat polymorphisms distributed across the autosomalgenome. Linkage was established with markers on the long armof chromosome 20. The highest observed LOD score was 5.54 ( 相似文献
4.
Patients with hereditary haemorrhagic telangiectasia (HHT, or Osler-Weber-Rendu syndrome) have variable presentation patterns and a high risk of preventable complications. Diagnostic tests for mutations in endoglin (HHT type 1) and ALK-1 (HHT type 2) are available. Some HHT patients are now known to have HHT-juvenile polyposis overlap syndrome due to Smad4 mutations. Families were ascertained following the presentation of probands for embolization of pulmonary arteriovenous malformations. Genome-wide linkage studies using over 700 polymorphic markers, and sequencing of candidate genes, were performed. In a previously described HHT family unlinked to endoglin or ALK-1, linkage to Smad4 was excluded, and no mutations were identified in the endoglin, ALK-1, or Smad4 genes. Two point LOD scores and recombination mapping identified a 5.4 cM HHT3 disease gene interval on chromosome 5 in which a single haplotype was inherited by all affected members of the pedigree. The remainder of the genome was excluded to a 2-5 cM resolution. We are currently studying a further family potentially linked to HHT3. We conclude that classical HHT with pulmonary involvement can result from mutations in an unidentified gene on chromosome 5. Identification of HHT3 should further illuminate HHT pathogenic mechanisms in which aberrant transforming growth factor (TGF)-beta signalling is implicated. 相似文献
5.
Morgan NV Bacchelli C Gissen P Morton J Ferrero GB Silengo M Labrune P Casteels I Hall C Cox P Kelly DA Trembath RC Scambler PJ Maher ER Goodman FR Johnson CA 《Journal of medical genetics》2003,40(6):431-435
Asphyxiating thoracic dystrophy (ATD), or Jeune syndrome, is a multisystem autosomal recessive disorder associated with a characteristic skeletal dysplasia and variable renal, hepatic, pancreatic, and retinal abnormalities. We have performed a genome wide linkage search using autozygosity mapping in a cohort of four consanguineous families with ATD, three of which originate from Pakistan, and one from southern Italy. In these families, as well as in a fifth consanguineous family from France, we localised a novel ATD locus (ATD) to chromosome 15q13, with a maximum cumulative two point lod score at D15S1031 (Zmax=3.77 at theta=0.00). Five consanguineous families shared a 1.2 cM region of homozygosity between D15S165 and D15S1010. Investigation of a further four European kindreds, with no known parental consanguinity, showed evidence of marker homozygosity across a similar interval. Families with both mild and severe forms of ATD mapped to 15q13, but mutation analysis of two candidate genes, GREMLIN and FORMIN, did not show pathogenic mutations. 相似文献
6.
A novel locus for non-syndromic sensorineural deafness (DFN6) maps to chromosome Xp22 总被引:4,自引:0,他引:4
del Castillo I; Villamar M; Sarduy M; Romero L; Herraiz C; Hernandez FJ; Rodriguez M; Borras I; Montero A; Bellon J; Tapia MC; Moreno F 《Human molecular genetics》1996,5(9):1383-1387
Non-syndromic X-linked deafness is highly heterogeneous. At least five
different clinical forms have been described, but only two loci have been
mapped. Here we report a Spanish family affected by a previously
undescribed X-linked form of hearing impairment. Deafness is non-
syndromic, sensorineural, and progressive. In affected males, the auditory
impairment is first detected at school age, affecting mainly the high
frequencies. Later it evolves to become severe to profound, involving all
frequencies for adulthood. Carrier females manifest a moderate hearing
impairment in the high frequencies, with the onset delayed to the fourth
decade of life. Deafness was assumed to be X- linked dominant, with
incomplete penetrance and variable expressivity in carrier females. The
family was genotyped for a set of microsatellite markers evenly spaced at
intervals of about 10 cM. We found evidence of linkage to markers in the
Xp22 region (maximum lod score of 5.30 at theta = 0.000 for DXS8036 and for
DXS8022). The position of the novel deafness locus (DFN6) was refined by
haplotype analysis. Mapping of the breakpoints in two critical recombinants
allowed us to define an interval for DFN6, delimited by DXS7108 on the
distal side and by DXS7105 on the proximal side, and spanning a genetic
distance of about 15 cM.
相似文献
7.
The gene for schnyder's crystalline corneal dystrophy maps to human chromosome 1p34.1-p36 总被引:3,自引:0,他引:3
Shearman AM; Hudson TJ; Andresen JM; Wu X; Sohn RL; Haluska F; Housman DE; Weiss JS 《Human molecular genetics》1996,5(10):1667-1672
Schnyder's crystalline corneal dystrophy (SCCD) is an autosomal dominant
eye disease characterized by a bilateral clouding of the central cornea,
arcus lipoides and/or visible crystalline deposits of cholesterol in the
stroma. There is accumulation of phospholipid, unesterified cholesterol and
cholesterol ester in the corneal stroma; this is believed to be due to an
imbalance in the local factors affecting lipid/cholesterol transport or
metabolism. The cellular mechanism of abnormal lipid transport and
metabolism in SCCD is of interest due to its potential involvement in
atherosclerosis, and its implications for the pathogenesis of
cerebrovascular, coronary and peripheral vascular disease as well as
corneal opacification. To determine the chromosomal location of the SCCD
locus, genome-wide linkage analysis has been performed in two large
Swede-Finn kindreds recently identified in central Massachusetts. After
analysing 300 microsatellite markers > 90% of the genome was excluded
from linkage to the SCCD locus. We now report the chromosomal assignment of
the gene for SCCD in both families to be 1p34.1-p36; the maximum multipoint
lod- score was 8.48 in the interval between D1S214 and D1S503. From
haplotype analysis, the SCCD locus lies in the 16 cM interval between
markers D1S2663 and D1S228. Several candidate genes for SCCD have been
localized to the 1p34.1-p36 interval.
相似文献
8.
Meeks M Walne A Spiden S Simpson H Mussaffi-Georgy H Hamam HD Fehaid EL Cheehab M Al-Dabbagh M Polak-Charcon S Blau H O'Rawe A Mitchison HM Gardiner RM Chung E 《Journal of medical genetics》2000,37(4):241-244
Primary ciliary dyskinesia is an autosomal recessive condition characterised by chronic sinusitis, bronchiectasis, and subfertility. Situs inversus occurs in 50% of cases (Kartagener syndrome). It has an estimated incidence of 1 in 20 000 live births. The clinical phenotype is caused by defective ciliary function associated with a range of ultrastructural abnormalities including absent dynein arms, absent radial spokes, and disturbed ciliary orientation. The molecular genetic basis is unknown. A genome scan was performed in five Arabic families. Using GENEHUNTER, a maximal multipoint lod score (HLOD) of 4.4 was obtained on chromosome 19q13.3-qter at alpha (proportion of linked families) = 0.7. A 15 cM critical region is defined by recombinations at D19S572 and D19S218. These data provide significant evidence for a PCD locus on chromosome 19q and confirm locus heterogeneity. 相似文献
9.
Bayrak-Toydemir P McDonald J Akarsu N Toydemir RM Calderon F Tuncali T Tang W Miller F Mao R 《American journal of medical genetics. Part A》2006,140(20):2155-2162
Hereditary hemorrhagic telangiectasia (HHT) is a genetically and clinically heterogeneous multisystem vascular dysplasia. Mutations of the endoglin and ACVRL1 genes are known to cause HHT. However, existence of HHT families in which linkage to these genes has been excluded has suggested that other gene(s) can cause HHT in some families. Recently, a family was reported to be linked to chromosome 5q, the HHT3 locus. Here we report on linkage results on a family with classic features of HHT, albeit a less severe phenotype with regards to epistaxis and telangiectases, in which linkage to HHT1, HHT2, and HHT3 is ruled out. Whole genome linkage analysis and fine mapping results suggested a 7 Mb region on the short arm of chromosome 7 (7p14) between STR markers D7S2252 and D7S510. We obtained a maximum two point LOD score of 3.60 with the STR marker D7S817. This region was further confirmed by haplotype analysis. These findings suggest the presence of another gene causing HHT (HHT4). The features in this family that strongly suggest the presence of a hereditary, multisystem vascular dysplasia would be easily missed during the typical evaluation and management of a patient with an AVM. This family helps emphasize the need to obtain a very detailed, targeted medical and family history for even mild, infrequent but recurring nosebleed, subtle telangiectases. Further studies of the candidate region and the identification of the gene responsible for the vascular anomalies in this family will add to our understanding of vascular morphogenesis and related disorders. 相似文献
10.
11.
A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31
Wali A John P Gul A Lee K Chishti MS Ali G Hassan MJ Leal SM Ahmad W 《Clinical genetics》2006,70(3):233-239
Congenital alopecia may occur either alone or in association with ectodermal and other abnormalities. On the bases of such associations, several different syndromes featuring congenital alopecia can be distinguished. Alopecia with mental retardation syndrome (APMR) is a rare autosomal recessive disorder, clinically characterized by total or partial hair loss and mental retardation. In the present study, a five-generation Pakistani family with multiple affected individuals with APMR was ascertained. Patients in this family exhibited typical features of APMR syndrome. The disease locus was mapped to chromosome 3q26.2-q26.31 by carrying out a genome scan followed by fine mapping. A maximum two-point logarithm of odds (LOD) score of 2.93 at theta=0.0 was obtained at markers D3S3053 and D3S2309. Multipoint linkage analysis resulted in a maximum LOD score of 4.57 with several markers, which supports the linkage. The disease locus was flanked by markers D3S1564 and D3S2427, which corresponds to 9.6-cM region according to the Rutgers combined linkage-physical map of the human genome (build 35) and contains 5.6 Mb. The linkage interval of the APMR locus identified here does not overlap with the one described previously; therefore, this locus has been designated as APMR2. 相似文献
12.
13.
Bönsch D Scheer P Neumann C Lang-Roth R Seifert E Storch P Weiller C Lamprecht-Dinnesen A Deufel T 《European journal of human genetics : EJHG》2001,9(3):165-170
Investigating a large German pedigree with non-syndromic hearing impairment of early onset and autosomal dominant mode of inheritance, linkage to known DFNA loci was excluded and in a subsequent genomic scan the phenotype was mapped to a 10-cM interval on chromosome 3q22; a maximum two-point lod score of 3.77 was obtained for the marker D3S1292. The new locus, DFNA18, is excluded from neighbouring deafness loci, DFNB15 and USH3, and it overlaps with the recently described DM2/PROMM locus. As hearing loss has been described as one feature of the PROMM phenotype, the DFNA18 gene might also be responsible for hearing loss in DM2/PROMM. 相似文献
14.
Barbet F Gerber S Hakiki S Perrault I Hanein S Ducroq D Tanguy G Dufier JL Munnich A Rozet JM Kaplan J 《European journal of human genetics : EJHG》2003,11(12):966-971
In contrast to the frequent dominant optic atrophies (DOAs) in which the neuropathy is usually an isolated event, isolated recessive optic atrophies (ROAs) are very uncommon and have been described as severe congenital or early infantile conditions. To date, two loci for isolated DOA have been mapped, of which one was ascribed to mutations in the OPA1 gene. Conversely, no isolated autosomal ROA locus had previously been localised. Here, we report a large multiplex consanguineous family of French origin affected with an early onset but slowly progressive form of isolated OA. A genome-wide search for homozygosity allowed the localisation of the disease-causing gene to chromosome 8q21-q22 (Zmax of 3.41 at theta=0 for D8S270), in a 12 Mb interval flanked by markers D8S1702 and D8S1794. This localisation excludes allelism of the disease with both isolated DOAs, on one hand, or all known syndromic forms of ROA, on the other hand, supporting the mapping of a first gene for isolated autosomal ROA (ROA1) on the long arm of chromosome 8. 相似文献
15.
Vincent P.; Plauchu H.; Hazan J.; Faure S.; Weissenbach J.; Godet J. 《Human molecular genetics》1995,4(5):945-949
Hereditary haemorrhagic telangiectasia (HHT) or Rendu-Osler-Weberdisease is an autosomal dominant vascular disorder which associatesepistaxis, mucocutaneous and visceral telangiectases, and recurrenthaemorrhage with chronic anaemia and visceral shuntings. Recently,the tumour growth factor (TGF)ß binding protein endoglinlocalized to 9q3334 was identified as responsible forHHT in several large kindreds with pulmonary arteriovenous malformations(PAVMs). Additional linkage studies demonstrated that HHT isa genetically heterogeneous disorder with families unlinkedto this region of 9q. In the families in which HHT was not linkedto chromosome 9, less PAVMs were present. Furthermore, in oneof these families, HHT was found linked to 3p22, where the TGFßII receptor is located. In this linkage study, we have analysed DNA from two families,In which HHT was unlinked to chromosome 9q and 3p, and PAVMswere absent, with a series of genetic markers on the centromericregion of chromosome 12. Using two-point linkage analysis, asignificant lod score of 2zmx = 7.86 at 相似文献
16.
Lamont RE Loredo-Osti J Roslin NM Mauthe J Coghlan G Nylen E Frappier D Innes AM Lemire EG Lowry RB Greenberg CR Triggs-Raine BL Morgan K Wrogemann K Fujiwara TM Zelinski T 《American journal of medical genetics. Part A》2005,(2):136-143
Bowen-Conradi syndrome (BCS) is a lethal autosomal recessive disorder with an estimated incidence of 1 in 355 live births in the Hutterite population. A few cases have been reported in other populations. Here, we report the results of a genome-wide scan and fine mapping of the BCS locus in Hutterite families. By linkage and haplotype analysis the BCS locus was mapped to a 3.5 cM segment (1.9 Mbp) in chromosome region 12p13.3 bounded by F8VWF and D12S397. When genealogical relationships among the families were taken into account in the linkage analysis, the evidence for linkage was stronger and the number of potentially linked regions was reduced to one. Under the assumption that all the Hutterite patients were identical by descent for a disease-causing mutation, haplotype analysis was used to infer likely historical recombinants and thereby narrow the candidate region to a chromosomal segment shared in common by all the affected children. This study also demonstrates that BCS and cerebro-oculo-facial-skeletal syndrome (COFS) are genetically distinct. 相似文献
17.
Aslam M Wajid M Chahrour MH Ansar M Haque S Pham TL Santos RP Yan K Ahmad W Leal SM 《American journal of medical genetics. Part A》2005,(1):18-22
A consanguineous family with autosomal recessive nonsyndromic hearing impairment (NSHI) was ascertained in Pakistan and displayed significant evidence of linkage to 3q13.31-q22.3. The novel locus (DFNB42) segregating in this kindred, maps to a 21.6 cM region according to a genetic map constructed using data from both the deCode and Marshfield genetic maps. This region of homozygosity is flanked by markers D3S1278 and D3S2453. A maximum multipoint LOD score of 3.72 was obtained at marker D3S4523. DFNB42 represents the third autosomal recessive NSHI locus to map to chromosome 3. 相似文献
18.
Héon E Greenberg A Kopp KK Rootman D Vincent AL Billingsley G Priston M Dorval KM Chow RL McInnes RR Heathcote G Westall C Sutphin JE Semina E Bremner R Stone EM 《Human molecular genetics》2002,11(9):1029-1036
We identified mutations in the VSX1 homeobox gene for two distinct inherited corneal dystrophies; posterior polymorphous dystrophy (PPD) and keratoconus. One of the mutation (R166W) responsible for keratoconus altered the homeodomain and impaired DNA binding. Two other sequence changes (L159M and G160D) were associated with keratoconus and PPD, respectively, and involved a region adjacent to the homeodomain. The G160D substitution, and a fourth defect affecting the highly conserved CVC domain (P247R), occurred in a child with very severe PPD who required a corneal transplant at 3 months of age. In this family, relatives with the G160D change alone had mild to moderate PPD, while P247R alone caused no corneal abnormalities. However, with either the G160D or P247R mutation, electroretinography detected abnormal function of the inner retina, where VSX1 is expressed. These data define the molecular basis of two important corneal dystrophies and reveal the importance of the CVC domain in the human retina. 相似文献
19.
A gene for autosomal recessive limb-girdle muscular dystrophy maps to chromosome 2p 总被引:10,自引:3,他引:10
Bashlr Rumaisa; Strachan Tom; Keers Sharon; Stephenson Anthea; Mahjneh Ibrahim; Marconi Giamplero; Nashef Lina; Bushby Kate M. D. 《Human molecular genetics》1994,3(3):455-457
The limb-girdle muscular dystrophies are a clinically and geneticallyheterogeneous group of disorders. We have ostudied two largeinbred families of different ethnic origin and excluded linkageto LGMD2 on chromosome 15q and SCARMD on chromosome 13. Proceedingto a genomic linkage search, we have now identified linkageto markers D2S134 and D2S136 on chromosome 2p (maximum lod score3.57 at zero recombination). The phenotype in the two familieswas similar, with onset in the pelvic girdle musculature inthe late teens and usually relatively slow progression. Thiswork Identifies a second locus for autosomal recessive limb-girdlemuscular dystrophy. 相似文献
20.
Pras E Mahler O Kumar V Frydman M Gefen N Pras E Hejtmancik JF 《Journal of medical genetics》2006,43(10):e50