A locus for autosomal dominant anterior polar cataract on chromosome 17p

Inherited cataract is a clinically and genetically heterogeneous disease. Here we report the identification of a new locus for an autosomal dominant anterior polar cataract on the short arm of chromosome 17. To map this new locus we performed genetic linkage analysis with microsatellite markers in a four-generation pedigree. After exclusion of seven candidate loci for cataract, we obtained significant positive LOD scores for markers D17S849 (Z = 4.01 / theta = 0.05) and D17S796 (Z = 4.17 / theta = 0.05). Multipoint analysis gave a maximum LOD score of 5.2 (theta max = 0.06) between these two markers. From haplotype analysis, the cataract locus lies in the 13 cM interval between markers D17S849 and D17S796. This study provides the first genetic mapping of an autosomal dominant anterior polar cataract.      

A locus for autosomal dominant posterior polar cataract on chromosome 1p

Autosomal dominant congenital cataract is a clinically and genetically heterogeneous lens disease. Here we report the linkage of a locus for autosomal dominant posterior polar cataract (CPP) to the distal short arm of chromosome 1. To map the CPP locus we performed molecular genetic linkage analysis using microsatellite markers in a three- generation pedigree. After exclusion of 13 known loci and candidate lens genes for autosomal dominant cataract, we obtained significantly positive LOD scores for markers D1S508 (Z = 3.14, theta = 0) and D1S468 (Z = 2.71, theta = 0). Multipoint analysis gave a maximum LOD score of 3.48 (theta = 0.07) between markers D1S508 and D1S468. From haplotype data, however, CPP probably lies in the telomeric interval D1S2845- 1pter, which includes the locus for the clinically distinct Volkman congenital cataract (CCV). This study provides the first evidence for genetic heterogeneity of autosomal dominant posterior polar cataract for which a locus had been linked previously to chromosome 16q.      

A locus for congenital preauricular fistula maps to chromosome 8q11.1-q13.3

The incidence of congenital preauricular fistula (CPF) is >1.1% in both Chinese and Caucasians, but it is even higher in Blacks. We mapped the locus for CPF to chromosome 8q11.1-q13.3 by linkage analysis of a family composed of 7 affected and 11 nonaffected members. The two-point LOD score was 2.40, shown by markers D8S285 and D8S1113 at a recombination fraction (theta) of 0.00. Results from three other markers (D8S1110, D8S260, and D8S1136) in the same region further support the linkage. Haplotype analysis for this family confined the locus to within an interval of approximately 26.7 cM, flanked by markers D8S532 and D8S279. A LOD score of <3 is likely due to the limitation of family size.     

Evidence for a type 1 diabetes susceptibility locus (IDDM10) on chromosome 10p11-q11 in a Russian population

Around 20 susceptibility loci for type 1 diabetes mellitus (T1DM) have been mapped. One of these loci, IDDM10, was found on chromosome 10p11-q11. Here, we investigated whether the IDDM10 locus contributes in the susceptibility to T1DM in a Russian family dataset. One hundred and fourteen simplex Russian families, each containing two siblings (one affected with T1DM diagnosed and one nondiabetic sibling), and 97 multiplex families, containing 106 affected full sibling pairs, were studied. Genomic DNA from the venous blood of the patients was genotyped by PCR using 12 microsatellites (D10S193, D10S548, D10S565, D10S586, D10S588, D10S675, D10S1243, D10S1426, D10S1733, D10S1772, D10S1780 and D10S1783) located on chromosome 10p11-q11. Using the multipoint linkage analysis, the region of suggestive linkage, with a multipoint logarithm of odds (LOD) ratio (MLS) value of more than 2.2, was found between markers D10S1733 and D10S1780, an area of 9.0 cM on the genetic map. The maximum linkage peak (MLS = 2.85 and nonparametric logarithm = 2.68) was observed between markers D11S565 and D11S1243. Using the transmission disequilibrium test, an association of these markers, D10S565 (P overall = 0.0082) and D10S1243 (P overall = 0.017), with T1DM was shown. These results suggest the evidence for the IDDM10 susceptibility locus on chromosome 10p11-q11.     

Evidence for a major susceptibility locus at 11q22.1-23.3 has been detected in a large Chinese family with pure grand mal epilepsy

Pure grand mal epilepsy (PGME) is a common subtype of idiopathic generalized epilepsy (IGE) with an unclear mode of inheritance. Several studies with the multiple families have provided evidence for the disorder to be linked to chromosome 8q24 and 8p. In this work, we performed an autosomal-wide scan linkage analysis using microsatellite markers in a large Chinese family with PGME and found seven markers with likelihood of odds (LOD), scores >/=1.0 (theta=0) in chromosome 11q22.1-23.3. The highest LOD score for two-point and multi-point linkage analysis are 1.99 (theta=0) at marker D11S4159 and 2.18 between markers D11S1782 and D11S3178, respectively, which reached the level of a suggested positive linkage LOD score (Z>/=1.9), under an autosomal dominant manner of inheritance with a penetrance of 65% but no significant positive LOD score (Z>/=3.3) was found after high density of microsatellite markers used in the regions. Obviously, our data do not support the linkage of the disease to chromosome 8q24 and 8p but implicate that chromosome 11q22.1-23.3 may be a new locus linked to PGME, which indicates the existence of genetic heterogeneity in the disorder.     

The mapping of DFNB62, a new locus for autosomal recessive non-syndromic hearing impairment, to chromosome 12p13.2-p11.23

Autosomal recessive non-syndromic hearing impairment (ARNSHI) is the most common form of prelingual inherited hearing impairment (HI). Here is described the mapping of a novel ARNSHI locus in a consanguineous Pakistani family with profound congenital HI. Two-point and multipoint linkage analyses were performed for the genome scan and fine mapping markers. Haplotypes were constructed to determine the region of homozygosity. At theta = 0, the maximum two-point LOD score of 4.0 was obtained at marker AAC040. A maximum multipoint LOD score of 5.3 was derived at marker D12S320, with the three-unit support interval demarcated by D12S89 and D12S1042. The region of homozygosity is flanked by markers D12S358 and D12S1042, which corresponds to 22.4 cM according to the Rutgers combined linkage-physical map of the human genome and spans 15.0 Mb on the sequence-based physical map. A novel ARNSHI locus DFNB62 was mapped to chromosome 12p13.2-p11.23. DFNB62 represents the second ARNSHI locus to map to chromosome 12.     

一个视网膜色素变性家系致病基因定位和CA4基因突变分析

目的通过对一个常染色体显性视网膜色素变性(autosomal dominant retinitis pigmentosa,adRP)家系致病基因的定位和基因突变分析,以确定该家系的致病基因及其突变形式。方法对15个已知的常染色体显性视网膜色素变性致病基因所在染色体位点进行连锁分析,以确定该家系与疾病连锁的染色体区域,对该区域附近候选基因进行直接序列分析。结果连锁分析提示在D17S701和D17S1604为正的连锁值(logofodds,LOD),分别为Zmax=2.107和Zmax=1.806。其余14个adRP染色体位点的微卫星标记两点LOD值均为负数。单倍型分析进一步将该家系致病基因定位于微卫星标记D17S916和D17S794之间的RP17位点,该位点adRP候选基因碳酸酐酶Ⅳ(carbonic anhydrase4,CA4)直接序列分析在其编码区未发现基因突变。结论将一个中国人常染色体显性视网膜色素变性家系的致病基因定位于RP17位点,但未发现该位点内的CA4基因突变,该家系是否存在CA4基因复杂突变或RP17位点是否存在新的视网膜色素变性致病基因有待于进一步研究。     

Fine mapping of the 5p13 locus linked to schizophrenia and schizotypal personality disorder in a Puerto Rican family

A locus involved in schizophrenia and related disorders in a Puerto Rican family has previously been mapped to chromosome 5p. The maximum two-point log of the odds (LOD) score of 3.72 was obtained for marker D5S111, and increased to 4.37 by multipoint analysis, assuming autosomal dominant inheritance with 90% penetrance. Additional genotyping and haplotype analysis placed the novel locus on 5p13.2-p13.3 within the interval between markers D5S1993 and D5S631. In the current study, we saturated the interval between markers D5S1993 and D5S631 with densely spaced polymorphic markers, genotyped these markers in the most informative branch of the family, and narrowed the critical region to 2.8 Mb. G-protein-coupled receptor gene [somatostatin and angiotensin-like peptide receptor (SALPR)] is one of the candidate genes within the critical interval. Sequence analysis of the coding region and the putative promoter of somatostatin and angiotensin-like peptide receptor did not reveal functionally significant variants in affected family members, although several polymorphisms were detected.     

A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31

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.     

一个中国手足裂畸形家系的遗传学分析

目的研究中国人手足裂畸形家系产生的分子遗传基础。方法通过X光片对一家系4代手足裂畸形患者进行了临床分析,采集了家系成员中18人的外周静脉血并提取基因组DNA。利用微卫星标记对该家系进行基因组扫描、连锁分析以及单倍型分析,并对于候选区域内的指趾发育相关基因Dactylin(DAC)基因的编码区、外显子/内含子交界区域以及部分的启动子区域进行测序分析。结果该家系大部分患者食指缺失或者发育不全,中指以缺指或以3、4并指出现,脚趾畸形程度略高于手指,表型特征符合已报道的手足裂畸形症的基本特征。两点间连锁分析在D10S192处获得最大的LOD值Z=3.50(θ=0.00),将该家系临床类型确定为SHFM3型手足裂畸形,单倍型分析将该家系的致病基因定位于D10S185和D10S1693之间约21cM的范围内,在对DAC基因测序中,未检测到任何的序列突变。结论通过对家系内表型分析,可将疾病类型确定为典型的手足裂畸形症,并将致病基因定位于10q23-q26约21cM范围内,测序结果显示DAC基因的点突变不是引发该家系手足裂畸形的原因。     

Replication and refinement of linkage of posterior polymorphous corneal dystrophy to the posterior polymorphous corneal dystrophy 1 locus on chromosome 20.

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.     

A novel locus for idiopathic generalized epilepsy in French-Canadian families maps to 10p11

Idiopathic generalized epilepsy (IGE) has evidence of a strong genetic etiology. We conducted genomewide linkage analysis for genes responsible for familial IGE in French-Canadian pedigrees. Twenty families segregating autosomal dominant epilepsy were collected. Four larger IGE families sufficiently powerful for independent linkage analysis were genome-scanned and follow-up fine mapping was performed over regions with LOD scores >3.0. The genotyping of 16 smaller families was carried out at significantly linked loci for supportive linkage analysis and haplotype comparisons. One of the four families provided a significant linkage result at marker D10S1426 on chromosome 10 (two-point LOD score = 3.05, theta = 0, multipoint LOD score = 3.18). Fine mapping revealed a segregating haplotype and key recombination breakpoints, suggesting a candidate gene interval of 6.5 Mb. Multipoint linkage analyses using the additional 16 families yielded a maximum LOD score under heterogeneity of 4.23 (alpha = 0.34) at this locus. Evaluation of recombination breakpoints in these families narrowed the candidate region to 1.7 Mb. Sequencing of the two known genes in this region, NRP1 and PARD3, was negative for mutation. Replication of linkage to this locus in other cohorts of IGE families is essential to characterize the underlying genetic mechanism for the disease.     

一个遗传性乳光牙本质家系致病基因的初步定位

目的：研究遗传性乳光牙本质家系致病基因是否与染色体４ｑ２１连锁。方法：提取在天津塘沽地区发现的一个遗传性乳光牙本质家系成员的外周血ＤＮＡ,选择染色体４ｑ２１上的４仆短串联重复序列多态性标记（ｓｈｏｒｔ ｔａｎｄｅｍ ｒｅｐｅａｔ ｐｏｌｙｍｏｒｐｈｉｓｍ,ＳＴＲＰ）：ＧＡＴＡ６２Ａ１１、ＤＳＰ（Ｐ）、ＳＰＰ１的Ｄ４Ｓ１５６３做荧光标记ＰＣＲ、等位片段分析,用Ｌｏｄ连锁分析法分析该家系致病基因位点与上述４个ＳＴＲ的连锁关系。结果：分别得到１３个家庭成员上述４个位点的基因型和单体型。ＭＬＩＮＫ软件分析显示：ＧＡＴＡ６２Ａ１１、ＫＳＰ（Ｐ）与致病基因位点连锁的最大Ｌｏｄ值分别为１．６３（θ＝０）。结论：遗传性乳光牙本质家系的致病基因初步定位在４号染色体上。     

Autosomal linkage analysis of a Japanese single multiplex schizophrenia pedigree reveals two candidate loci on chromosomes 4q and 3q.

We analyzed a large multiplex schizophrenia pedigree collected in mid-eastern Japan using 322 microsatellite markers distributed throughout the whole autosome. Under an autosomal-dominant inheritance model, the highest pairwise LOD score (LOD = 1.69) was found at 4q (D4S2431: theta = 0.0), and LOD scores at two other loci 3q (ATA34G06) and 8q (D8S1128) were 1.62 and 1.46, respectively. In multipoint analysis, LOD scores of the regions on 4q and 3q remained at a similar level; however, the LOD score of the region on 8q apparently decreased. Additional dense map analysis revealed haplotypes on 4q and 3q regions shared by affected individuals. On chromosome 4q, the haplotype spanning about 8 centiMorgans (cM) was shared by four of six genotyped individuals with schizophrenia and one affected individual whose haplotype was estimated. On 3q, the haplotype spanning about 20 cM was shared by five genotyped individuals with schizophrenia. We obtained two candidate regions of major susceptibility loci for schizophrenia on chromosomes 3q and 4q.     

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.     

No evidence for linkage between schizophrenia and markers at chromosome 15q13-14

Freedman et al. [1997: Proc Natl Acad Sci USA 94:587-592] reported linkage in nine multiplex schizophrenia families to markers on chromosome 15, using impaired neuronal inhibition to repeated auditory stimuli (P50), a neurophysiological deficit associated with schizophrenia, as the phenotype. The highest LOD score obtained (5.3 at theta = 0) was for marker D15S1360 mapped to chromosome 15q13-14, less than 120 kb from the alpha7-nicotinic receptor (CHRNA7) gene. The study also reported a small positive LOD score for D15S1360 when examined for linkage to the schizophrenia phenotype. Following these findings, we examined three polymorphic markers (D15S1360, L76630, and ACTC) on chromosome 15q13-14 near the CHRNA7 gene for linkage to schizophrenia, using 54 pedigrees from an independent study. Alleles for these three markers were genotyped and analyzed using parametric and nonparametric methods. No LOD score above 1.00 was obtained for any marker, and affected sib-pair analysis likewise showed no evidence for linkage. We conclude that in our families the region around the CHRNA7 locus does not contain a major locus for susceptibility to schizophrenia.     

A novel locus for autosomal dominant hereditary gingival fibromatosis, GINGF3, maps to chromosome 2p22.3-p23.3

Hereditary gingival fibromatosis (HGF) is a rare, benign disorder characterized by slowly progressive fibrous overgrowth of the gingiva. To date, two loci have been mapped in familial cases with autosomal dominant non-syndromic HGF: GINGF (MIM 135300) on chromosome 2p21-p22 and GINGF2 (MIM 605544) on chromosome 5q13-q22. Of the two loci, only SOS1 (son of sevenless one, MIM 182530) gene underlying GINGF locus has been identified. Ascertainment of a large Chinese family has allowed the mapping of a novel locus to 2p22.3-p23.3, GINGF3. Haplotype construction and analysis localized the new locus to an 11.4-cM interval between markers D2S2221 (telomeric) and D2S1788 (centromeric). The maximum two-point limit of detection (LOD) score of 3.45 (theta=0) and multipoint LOD score of 5.00 for marker D2S390 strongly supported linkage to this region. Thus, this genetic interval is distal to and does not overlap with the previously described locus, GINGF, on 2p21-p22.     

Characterization of a susceptibility locus for SLE, SLEB5, on chromosome 4p14-13

Systemic lupus erythematosus is a systemic autoimmune disorder of unknown aetiology but is most likely caused by an interaction between several genetic factors and the environment. In a previously published genome scan we presented linkage to a marker on chromosome 4p13 in Icelandic families. Fine mapping of the region has been performed using 10 multicase families from Iceland and the maximum two-point LOD score was given by marker D4S2974 (Z = 3.57, alpha = 1). Multipoint analyses of the markers in the region suggest a putative disease gene to be located between markers D4S405 and D4S2381. The maximum multipoint LOD score (Z = 3.76) was given for marker D4S2974 in combination with the novel repeat GT4C2. A family-specific haplotype was segregating with the disease in each of eight families although a founder haplotype could not be identified. Analysis of recombination events in the patients delimited the susceptibility locus to approximately 3 cM. The susceptibility locus identified probably contains a mutation that has been enriched in the Icelandic population but is less common in other populations. We also show that this region is not identical to a susceptibility locus for SLE located on 4p16 where we detect no linkage.     

Hereditary lymphedema: evidence for linkage and genetic heterogeneity

Hereditary or primary lymphedema is a developmental disorder of the lymphatic system which leads to a disabling and disfiguring swelling of the extremities. Hereditary lymphedema generally shows an autosomal dominant pattern of inheritance with reduced penetrance, variable expression and variable age at onset. Three multigeneration families demonstrating the phenotype of hereditary lymphedema segregating as an autosomal dominant trait with incomplete penetrance were genotyped for 366 autosomal markers. Linkage analysis yielded a two-point LOD score of 6.1 at straight theta = 0. 0 for marker D5S1354 and a maximum multipoint LOD score of 8.8 at marker D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional families using markers from the linked region showed one family consistent for linkage to distal chromosome 5. In the second family, linkage to 5q was excluded for all markers in the region with LOD scores Z < -2.0. The vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the linked region, and partial sequence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family. This study localizes a gene for primary lymphedema to distal chromosome 5q, identifies a plausible candidate gene in the linked region, and provides evidence for a second, unlinked locus for primary lymphedema.