The breakpoint on 7p in a patient with t(6;7) and craniosynostosis is spanned by a YAC clone containing the D7S503 locus

We previously reported a patient with an apparently balanced t(6;7) translocation and craniosynostosis. We now demonstrate, by fluorescence in situ hybridization, that the yeast artificial chromosome clone 933_e_l from the Centre d'Etude du Polymorphisme Humain library harbouring the D7S503 locus spans the breakpoint on distal 7p. Recent reports have defined a candidate region for a Saethre-Chotzen craniosynostosis locus between the loci D7S513 and D7S516, a region that includes the D7S503 locus. Since the translocation carrier shows only some of the symptoms characteristic for the Saethre-Chotzen syndrome, it remains unresolved whether the gene disrupted by the translocation event is the only one causing craniosynostosis in this chromosomal region.     

Evidence That the Saethre-Chotzen Syndrome Locus Lies between D7S664 and D7S507, by Genetic Analysis and Detection of a Microdeletion in a Patient

The locus for Saethre-Chotzen syndrome, a common autosomal dominant disorder of craniosynostosis and digital anomalies, was previously mapped to chromosome 7p between D7S513 and D7S516. We used linkage and haplotype analyses to narrow the disease locus to an 8-cM region between D7S664 and D7S507. The tightest linkage was to locus D7S664 ( = 7.16, θ = .00). Chromosomes from a Saethre-Chotzen syndrome patient with t(2;7) (p23;p22) were used for in situ hybridization with YAC clones containing D7S664 and D7S507. The D7S664 locus was found to lie distal to the 7p22 breakpoint, and the D7S507 locus was deleted from the translocation chromosomes. These genetic and physical mapping data independently show that the disease locus resides in this interval.     

Possible genetic heterogeneity in the Saethre-Chotzen syndrome

Saethre-Chotzen syndrome is an autosomal dominant acrocephalosyndactyly syndrome whose gene has been assigned to chromosome 7p. Cytogenetic and linkage analyses have enabled the interval encompassing the disease gene to be delimited to a short region of chromosome 7p15.3–p21.2. Based on the genetic analysis of three unreported families, we confirm the location of the disease gene(s) in the interval defined by loci D7S664 and D7S493 (Z_max = 4.78 at * = 0 at the D7S488 locus) but fail to decide whether one or more disease-causing genes map in this genetic interval. Received: 2 January 1996 / Revised: 21 March 1996     

Localization of a gene for autosomal dominant Larsen syndrome to chromosome region 3p21.1-14.1 in the proximity of,but distinct from,the COL7A1 locus.

Larsen syndrome (LS) is a skeletal dysplasia (osteochondrodysplasia) in which multiple dislocations of the large joints are the major feature. Nosology in this group of diseases, which constitutes 8% of Mendelian disorders in man, is primarily based on clinical and radiographic features. Hopes for more accurate classification grounds are currently being met by progress in elucidation of underlying genetic defects. We have performed linkage analysis in a large Swedish kindred with autosomal dominant LS and found the gene (LAR1) to be strongly linked to chromosome 3p markers (Zmax = 13.4 at (theta = .00). Recombination analysis indicates that the LAR1 locus is located in a region defined distally by D3S1581 and proximally by D3S1600, which cytogenetically maps to chromosome region 3p21.1-14.1. Linkage and recombination analysis of a COL7A1 PvuII intragenic polymorphism versus LS and chromosome 3 markers indicate that COL7A1 is located close to, but distinct from, the LAR1 locus.     

Tightly linked flanking microsatellite markers for the Usher syndrome type I locus on the short arm of chromosome 11.

Usher syndrome type I is an autosomal recessive disease characterized by profound congenital hearing impairment and vestibular dysfunction followed by the onset of progressive pigmentary retinopathy in childhood or early adolescence. A locus (USH1C) for one form of this disease was previously assigned to the short arm of chromosome 11 through linkage studies in the Acadian population of southwestern Louisiana. Linkage analyses of a set of microsatellite markers in 27 Acadian families provide evidence that USH1C lies between D11S861 and D11S928. Three markers (D11S419, D11S921, and D11S899) that lie between the flanking markers show no recombination with USH1C, and all 54 chromosomes with the abnormal allele at the disease locus have identical alleles for D11S419 and D11S921. This haplotype was found on only 10 of 50 chromosomes with the normal allele at the disease locus, suggesting a strong founder effect. Of the 54 chromosomes with the abnormal allele, 12 had a divergent allele at D11S899. These results suggest that USH1C is in the 2-3-cM interval between D11S861 and D11S899.     

Homozygosity mapping of a Weill-Marchesani syndrome locus to chromosome 19p13.3-p13.2

Weill-Marchesani syndrome (WMS) is a rare disease characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities, including microspherophakia, ectopia lentis, and glaucoma. Both autosomal recessive and autosomal dominant modes of inheritance have been described in association with WMS. We have performed a genome-wide search in two large consanguineous families of Lebanese and Saudian origin consistent with an autosomal recessive mode of inheritance. Here, we report the linkage of the disease gene to chromosome 19p13.3-p13.2 (Zmax=5.99 at theta=0 at locus D19S906). A recombination event between loci D19S905 and D19S901 defines the distal boundary, and a second recombination event between loci D19S221 and D19S840 defines the proximal boundary of the genetic interval encompassing the WMS gene (12.4 cM). We hope that our ongoing studies will lead to the identification of the disease-causing gene.     

Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23.

Fetal hemoglobin (Hb F) and fetal cell (FC) levels in adults show considerable variation and are influenced by several genetic variants; the major determinants appear to be unlinked to the beta-globin gene cluster. Recently, a trans-acting locus controlling Hb F and FC production has been mapped to chromosome 6q23 in an Asian Indian kindred that includes individuals with heterocellular hereditary persistence of Hb F (HPFH) associated with beta thalassemia. We have extended the kindred by 57 members, bringing the total studied to 210, and have saturated the region with 26 additional markers. Linkage analysis showed tight linkage of the quantitative-trait locus (QTL) to the anonymous markers D6S976 (LOD score 11.3; recombination fraction .00) and D6S270 (LOD score 7.4; recombination fraction .00). Key recombination events now place this QTL within a 1-2-cM interval spanning approximately 1.5 Mb between D6S270 and D6S1626. Furthermore, haplotype analysis has led to a reevaluation of the genealogy and to the identification of additional relationships in the kindred.     

Genetic mapping of DNA segments relative to the locus for the fragile-X syndrome at Xq27.3.

We have tested linkage between the locus for the fragile-X [fra(X)] syndrome at Xq27.3 and five polymorphic restriction sites identified by four DNA probes mapping distal to Xq26.1. A maximum distance of approximately 15 centimorgans (cM) between Xq27.3 and the marker loci mapping to this region was predicted based on the physical chromosome length. Close linkage between the disease and marker loci was excluded for probes DXS19 and DXS37 (theta = .05, Z = -2.94 and Z = -4.17, respectively). These marker loci were estimated to be less than five cM apart but approximately 40 cM proximal to the fragile site, indicating that there is a significantly greater frequency of recombination in this region of the X chromosome than expected from the physical length. Linkage results for the other marker loci and the fra(X) syndrome were inconclusive. However, the pX45d probe locus appears very closely linked to the factor IX locus (Z = 1.94 at theta = 0) and is approximately 20 cM proximal to Xq27.3. A relative map of the polymorphic restriction sites, fra(X) syndrome locus, and factor IX locus was constructed by maximizing lod scores over the Xq26.1----q27.3 region.     

D19S51 is closely linked with and maps distal to the myotonic dystrophy locus on 19q.

Recent genetic linkage studies have mapped the myotonic dystrophy (DM) locus to 19q13.3. All closely linked DM markers identified to date have been located on the centromeric side of the disease locus, with a relatively large genetic interval (9 cM) observed between the nearest distal marker and DM. We show here that the recently described marker p134C is tightly linked to DM (peak lod score 35.8 at peak recombination fraction .006) and confirm the previous suggestion that the p134C locus, D19S51 maps distal to the disease locus. D19S51 and the closest proximal flanking loci, ERCC1 and D19S115 (pE0.8), define a small genetic interval of less than 2 cM that contains the DM locus.     

Assignment of the tibial muscular dystrophy locus to chromosome 2q31.

Tibial muscular dystrophy (TMD) is a rare autosomal dominant distal myopathy with late adult onset. The phenotype is relatively mild: muscle weakness manifests in the patient's early 40s and remains confined to the tibial anterior muscles. Histopathological changes in muscle are compatible with muscular dystrophy, with the exception that rimmed vacuoles are a rather common finding. We performed a genomewide scan, with 279 highly polymorphic Cooperative Human Linkage Center microsatellite markers, on 11 affected individuals of one Finnish TMD family. The only evidence for linkage emerged from markers in a 43-cM region on chromosome 2q. In further linkage analyses, which included three other Finnish TMD families and which used a denser set of markers, a maximum two-point LOD score of 10.14 (recombination fraction of .05) was obtained with marker D2S364. Multipoint likelihood calculations, combined with the haplotype and recombination analyses, restricted the TMD locus to an approximately 1-cM critical chromosomal region without any evidence of heterogeneity. Since all the affecteds share one core haplotype, the dominance of one ancestor mutation is obvious in the Finnish TMD families. The disease locus that was found represents a novel muscular dystrophy locus, providing evidence for the involvement of one additional gene in the distal myopathy group of muscle disorders.     

Chromosomal deletion 4p15.32----p14 in a Treacher Collins syndrome patient: exclusion of the disease locus from and mapping of anonymous DNA sequences to this region.

Treacher Collins syndrome is an autosomal dominant condition of bilateral craniofacial abnormalities of structures derived from the first and second branchial arches. A patient with severe manifestations of Treacher Collins syndrome and a de novo chromosomal deletion in region 4p15.32----p14 was identified. Anonymous DNA sequences of loci D4S18, D4S19, D4S20, D4S22, and D4S23 were mapped to the deleted region. DNA probes previously mapped to loci on chromosome 4p (D4S10, D4S15, D4S16, D4S26, D4S35, D4S95, D4S144, RAF1P1, QDPR, and HOX7) were not deleted in this patient. Linkage analysis between the D4S18, D4S23, and QDPR loci and Treacher Collins syndrome in eight families excluded the Treacher Collins syndrome locus from the region of the deletion.     

Mapping the Wilson disease locus to a cluster of linked polymorphic markers on chromosome 13.

Linkage of both several chromosome 13 DNA markers and the locus for the red cell enzyme esterase D (ESD) to Wilson disease (WD), an autosomal recessive disorder affecting copper metabolism, was investigated in five Middle-Eastern kindreds. The single-copy probe 7D2, identifying the polymorphic region D13S10, was demonstrated to lie 7.5 centiMorgans (cM) from the locus, since a maximum lod score of 4.66 at a recombination frequency of .07 (7.5 cM) was found between the locus for WD (WND) and D13S10. Multipoint linkage analysis between several chromosome 13 markers and WND enables us to propose that the order of markers closely linked to WND is as follows: centromere-D13S10-ESD-WND.     

Evidence for a major gene (RP10) for autosomal dominant retinitis pigmentosa on chromosome 7q: linkage mapping in a second,unrelated family

Retinitis pigmentosa is a genetically heterogeneous form of retinal degeneration, which has X-linked, autosomal recessive and autosomal dominant forms. The disease genes in families with autosomal dominant retinitis pigmentosa (adRP) have been linked to six loci, on 3q, 6p, 7p, 7q, 8q and 19q. In a large American family with late-onset adRP, microsatellite markers were used to test for linkage to the loci on 3q, 6p, 7p, 7q and 8q. Linkage was found to 7q using the marker D7S480. Additional microsatellite markers from 7q were then tested. In total, five markers, D7S480, D7S514, D7S633, D7S650 and D7S677, show statistically significant evidence for link-age in this family, with a maximum two-point lod score of 5.3 at 0% recombination from D7S514. These results confirm an earlier report of linkage to an adRP locus (RP10) in an unrelated family of Spanish origin and indicate that RP10 may be a significant gene for inherited retinal degeneration. In addition, we used recently reported microsatellite markers from 7q to refine the linkage map of the RP10 locus.     

A gene for autosomal recessive limb-girdle muscular dystrophy in Manitoba Hutterites maps to chromosome region 9q31-q33: evidence for another limb-girdle muscular dystrophy locus.

Characterized by proximal muscle weakness and wasting, limb-girdle muscular dystrophies (LGMDs) are a heterogeneous group of clinical disorders. Previous reports have documented either autosomal dominant or autosomal recessive modes of inheritance, with genetic linkage studies providing evidence for the existence of at least 12 distinct loci. Gene products have been identified for five genes responsible for autosomal recessive forms of the disorder. We performed a genome scan using pooled DNA from a large Hutterite kindred in which the affected members display a mild form of autosomal recessive LGMD. A total of 200 markers were used to screen pools of DNA from patients and their siblings. Linkage between the LGMD locus and D9S302 (maximum LOD score 5.99 at recombination fraction .03) was established. Since this marker resides within the chromosomal region known to harbor the gene causing Fukuyama congenital muscular dystrophy (FCMD), we expanded our investigations, to include additional markers in chromosome region 9q31-q34.1. Haplotype analysis revealed five recombinations that place the LGMD locus distal to the FCMD locus. The LGMD locus maps close to D9S934 (maximum multipoint LOD score 7.61) in a region that is estimated to be approximately 4.4 Mb (Genetic Location Database composite map). On the basis of an inferred ancestral recombination, the gene may lie in a 300-kb region between D9S302 and D9S934. Our results provide compelling evidence that yet another gene is involved in LGMD; we suggest that it be named "LGMD2H."     

Mapping the Treacher Collins syndrome locus to 5q31.3----q33.3.

Treacher Collins syndrome is an autosomal dominant disorder of abnormal craniofacial development. Linkage analysis was performed in Treacher Collins families with restriction fragment length or microsatellite polymorphisms associated with eight loci previously mapped to 5q31----qter. Positive lod scores were obtained for four loci, D5S119, D5S207, D5S209, and D5S210, which map to 5q31.3----q33.3. The Treacher Collins syndrome locus was linked closest to locus D5S210, which is associated with microsatellite polymorphisms, with a maximum lod score of 8.65 at theta = 0.02. The Treacher Collins syndrome locus was excluded from locus ADRB2R, which maps to 5q31----q32, and loci D5S22, D5S61, and D5S43, which map to 5q34----qter. There was no evidence for genetic heterogeneity among eight families with variable expression of the condition.     

A locus for X-linked congenital stationary night blindness is located on the proximal portion of the short arm of the X chromosome

Summary Linkage between X-linked congenital stationary night blindness (CSNB1) and seven markers on the X chromosome was investigated in a large four-generation Albertan kindred. We detected significant linkage between the CSNB1 locus and the locus DXS255 (maximum lod score = 6.73 at a recombination fraction of 6%; confidence interval of 1% to 18%), which anchors the CSNB1 locus to the proximal region near p11.22 on the short arm of the X chromosome.     

Mapping of the von Hippel-Lindau disease locus to a small region of chromosome 3p by genetic linkage analysis.

Genetic linkage studies were performed in 22 families with von Hippel-Lindau (VHL) disease by using polymorphic DNA markers from distal chromosome 3p. Linkage was detected between VHL disease and the markers D3S18 (Zmax = 6.6 at theta = 0.0, confidence interval (CI) 0.00-0.06), RAF1 (Zmax = 5.9 at theta = 0.06, CI 0.01-0.16), and THRB (Zmax 3.4 at theta = 0.11). Multipoint linkage analysis localized the VHL disease gene within a small region (approximately 8 cM) of 3p25-p26 between RAF1 and (D3S191, D3S225) and close to the D3S18 locus. There was no evidence of locus heterogeneity, and families with and without pheochromocytoma showed linkage to D3S18. The identification of DNA markers flanking the VHL disease gene allows reliable presymptomatic and prenatal diagnosis to be offered to informative families.     

Evidence for genetic heterogeneity in hereditary hydronephrosis caused by pelvi-ureteric junction obstruction,with one locus assigned to chromosome 6p

Summary Hereditary hydronephrosis (MIM 143400) is an autosomal dominant trait that causes unilateral or bilateral pelvi-ureteric junction (PUJ) obstruction. Linkage analysis was undertaken in 5 families with hereditary PUJ obstruction using the major histocompatibility complex locus as a test marker. The data as a whole supported a hereditary hydronephrosis locus on 6p. Maximal lod scores were 3.090 at a recombination fraction of 0.1 with full penetrance, and 2.486 at a recombination fraction of 0.1 with a penetrance of 90%. However, analysis of two point lod scores using the HOMOG program revealed significant evidence for genetic heterogeneity with one locus on 6p in 4 of the families, and a different locus in one family. After exclusion of this unlinked family, two point analysis gave a maximal lod score of 3.9 at a recombination fraction of 0.05 with full penetrance, and 4.2 at a recombination fraction of 0.0 with 90% penetrance. These data support the assignment of one of the loci for hereditary hydronephrosis to chromosome 6p.     

Map refinement of locus RP13 to human chromosome 17p13.3 in a second family with autosomal dominant retinitis pigmentosa.

In order to elucidate the genetic basis of autosomal dominant retinitis pigmentosa (adRP) in a large eight-generation family (UCLA-RP09) of British descent, we assessed linkage between the UCLA-RP09 adRP gene and numerous genetic loci, including eight adRP candidate genes, five anonymous adRP-linked DNA loci, and 20 phenotypic markers. Linkage to the UCLA-RP09 disease gene was excluded for all eight candidate genes analyzed, including rhodopsin (RP4) and peripherin/RDS (RP7), for the four adRP loci RP1, RP9, RP10 and RP11, as well as for 17 phenotypic markers. The anonymous DNA marker locus D17S938, linked to adRP locus RP13 on chromosome 17p13.1, yielded a suggestive but not statistically significant positive lod score. Linkage was confirmed between the UCLA-RP09 adRP gene and markers distal to D17S938 in the chromosomal region 17p13.3. A reanalysis of the original RP13 data from a South African adRP family of British descent, in conjunction with our UCLA-RP09 data, suggests that only one adRP locus exists on 17p but that it maps to a more telomeric position, at band 17p13.3, than previously reported. Confirmation of the involvement of RP13 in two presumably unrelated adRP families, both of British descent, suggests that this locus is a distinct adRP gene in a proportion of British, and possibly other, adRP families.     

Confirmation of linkage of Duane's syndrome and refinement of the disease locus to an 8.8-cM interval on chromosome 2q31

Duane's syndrome is a congenital abnormality of eye movement, which may be inherited as an autosomal dominant trait but usually occurs sporadically. Genetic mapping in a Mexican family has recently identified a locus for Duane's syndrome within a 17.8-cM region of chromosome 2q31. The region was flanked by the microsatellite markers D2S2330 and D2S364. We performed linkage and haplotype analysis in a four-generation UK family with autosomal dominant transmission of Duane's syndrome. Linkage to 2q31 was confirmed with a maximum logarithm of differences (lod) score of 3.3 at theta = 0. The genetic interval was reduced to an 8.8-cM region between markers D2S326 and D2S364 that includes the candidate homeobox D gene cluster.