A locus for brachydactyly type A-1 maps to chromosome 2q35-q36

Brachydactyly type A-1 (BDA1) was, in 1903, the first recorded example of a human anomaly with Mendelian autosomal dominant inheritance. Two large families, the affected members of which were radiographed, were recruited in the study we describe here. Two-point linkage analysis for pedigree 1 (maximum LOD score [Zmax] 6.59 at recombination fraction [theta] 0.00) and for pedigree 2 (Zmax=5.53 at straight theta=0.00) mapped the locus for BDA1 in the two families to chromosome 2q. Haplotype analysis of pedigree 1 confined the locus for family 1 within an interval of <8.1 cM flanked by markers D2S2248 and D2S360, which was mapped to chromosome 2q35-q36 on the cytogenetic map. Haplotype analysis of pedigree 2 confined the locus for family 2 within an interval of <28. 8 cM flanked by markers GATA30E06 and D2S427, which was localized to chromosome 2q35-q37. The two families had no identical haplotype within the defined region, which suggests that the two families were not related.     

A novel form of "central pouchlike" cataract, with sutural opacities, maps to chromosome 15q21-22

Congenital cataract is a clinically and genetically highly heterogeneous eye disorder, with autosomal dominant inheritance being most common. We investigated a large seven-generation family with 74 individuals affected by autosomal dominant congenital cataract (ADCC). The phenotype in this family can be described as "central pouchlike" cataract with sutural opacities, and it differs from the other mapped cataracts. We performed linkage analysis with microsatellite markers in this family and excluded the known candidate genes. A genomewide search revealed linkage to markers on chromosome 15, with a maximum two-point LOD score of 5.98 at straight theta=0 with marker D15S117. Multipoint analysis also gave a maximum LOD score of 5.98 at D15S117. Multipoint and haplotype analysis narrowed the cataract locus to a 10-cM region between markers D15S209 and D15S1036, closely linked to marker D15S117 in q21-q22 region of chromosome 15. This is the first report of a gene for a clinically new type of ADCC at 15q21-22 locus.     

A new locus for autosomal recessive hereditary spastic paraplegia maps to chromosome 16q24.3.

Hereditary spastic paraplegia is a genetically and phenotypically heterogeneous disorder. Both pure and complicated forms have been described, with autosomal dominant, autosomal recessive, and X-linked inheritance. Various loci (SPG1-SPG6) associated with this disorder have been mapped. Here, we report linkage analysis of a large consanguineous family affected with autosomal recessive spastic paraplegia with age at onset of 25-42 years. Linkage analysis of this family excluded all previously described spastic paraplegia loci. A genomewide linkage analysis showed evidence of linkage to chromosome 16q24.3, with markers D16S413 (maximum LOD score 3.37 at recombination fraction [theta] of .00) and D16S303 (maximum LOD score 3.74 at straight theta=.00). Multipoint analysis localized the disease gene in the most telomeric region, with a LOD score of 4.2. These data indicate the presence of a new locus linked to pure recessive spastic paraplegia, on chromosome 16q24.3, within a candidate region of 6 cM.     

A novel dysmorphic syndrome with open calvarial sutures and sutural cataracts maps to chromosome 14q13-q21

We describe a new dysmorphic syndrome in an inbred Saudi Arabian family with 21 members. Five males and one female have similar craniofacial features including wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. In addition, these individuals have Y-shaped sutural cataracts diagnosed by 1-2 years of age. No chromosomal or biochemical abnormalities were identified. A genome-wide scan was performed, and two-point LOD score analysis, assuming autosomal recessive inheritance, detected linkage to chromosome 14q13-q21. The highest LOD scores were obtained for marker GATA136A04 (LOD=4.58 at theta=0.00) and for the adjacent telomeric marker D14S1048 (LOD=4.32 at theta=0.00). Multipoint linkage analysis resulted in a maximum LOD score of 5.44 between markers D14S1048 and GATA136A04. Model independent analysis by SIBPAL confirmed linkage to the same chromosomal region. Haplotype analysis indicated that all affected individuals were homozygous for the interval on chromosome 14q13-q21 with two recombinants for D14S1014 (centromeric) and one recombinant for D14S301 (telomeric). These recombinations limit the disease locus to a region of approximately 7.26 Mb. Candidate genes localized to this region were identified, and analysis of PAX9 did not identify mutations in these patients. The unique clinical phenotype and the mapping data suggest that this family represents a novel autosomal recessive syndrome.     

Mapping of a First Locus for Autosomal Dominant Myxomatous Mitral-Valve Prolapse to Chromosome 16p11.2-p12.1

Myxomatous mitral-valve prolapse (MMVP), also called Barlow disease, is a common cardiac abnormality and affects up to 5% of the population. It is characterized by an excess of tissue that leads to billowing of the mitral leaflets, sometimes complicated by prolapse. Typical histological findings include myxomatous degeneration and degradation of collagen and elastin. Previous reports have proposed an autosomal dominant inheritance of the trait, with age- and sex-dependent expression. By systematic echocardiographic screening of the first-degree relatives of 17 patients who underwent mitral-valve repair, we have identified four pedigrees showing such an inheritance. Genomewide linkage analysis of the most informative pedigree (24 individuals, three generations) showed a significant linkage for markers mapping to chromosome 16p, with a two-point maximum LOD score for D16S3068 (Zmax=3.30 at straight theta=0). Linkage to D16S3068 was confirmed in a second family (Zmax=2.02 at straight theta=0) but was excluded for the two remaining families, thus demonstrating the genetic heterogeneity of the disease. Multipoint linkage analysis performed, with nine additional markers, on the two families with linkage gave maximum multipoint LOD scores of 5.45 and 5.68 for D16S3133, according to a conservative and a stringent model, respectively. Haplotype analysis defined a 5-cM minimal MMVP-1 locus between D16S3068 (16p11.2) and D16S420 (16p12. 1) and a 34-cM maximal interval between D16S404 and D16S3068 when recombination events were taken into account only in affected individuals. The identification of this locus represents a first step toward a new molecular classification of mitral-valve prolapse.     

Mapping of a new locus for autosomal recessive demyelinating Charcot-Marie-Tooth disease to 19q13.1-13.3 in a large consanguineous Lebanese family: exclusion of MAG as a candidate gene

Autosomal recessive Charcot-Marie-Tooth disease (CMT) type 4 (CMT4) is a complex group of demyelinating hereditary motor and sensory neuropathies presenting genetic heterogeneity. Five different subtypes that correspond to six different chromosomal locations have been described. We hereby report a large inbred Lebanese family affected with autosomal recessive CMT4, in whom we have excluded linkage to the already-known loci. The results of a genomewide search demonstrated linkage to a locus on chromosome 19q13.1-13.3, over an 8.5-cM interval between markers D19S220 and D19S412. A maximum pairwise LOD score of 5.37 for marker D19S420, at recombination fraction [theta].00, and a multipoint LOD score of 10.3 for marker D19S881, at straight theta = .00, strongly supported linkage to this locus. Clinical features and the results of histopathologic studies confirm that the disease affecting this family constitutes a previously unknown demyelinating autosomal recessive CMT subtype known as "CMT4F." The myelin-associated glycoprotein (MAG) gene, located on 19q13.1 and specifically expressed in the CNS and the peripheral nervous system, was ruled out as being the gene responsible for this form of CMT.     

Genetic linkage mapping of multiple epiphyseal dysplasia to the pericentromeric region of chromosome 19.

Multiple epiphyseal dysplasia (MED) is an inherited chondrodystrophy that results in deformity of articular surfaces and in subsequent degenerative joint disease. The disease is inherited as an autosomal dominant trait with high penetrance. An MED mutation has been mapped by genetic linkage analysis of DNA polymorphisms in a single large pedigree. Close linkage of MED to 130 tested chromosomal markers was ruled out by discordant inheritance patterns. However, strong evidence for linkage of MED to markers in the pericentromeric region of chromosome 19 was obtained. The most closely linked marker was D19S215, with a maximum LOD score of 6.37 at theta = .05. Multipoint linkage analysis indicated that MED is located between D19S212 and D19S215, a map interval of 1.7 cM. Discovery of the map location of MED in this family will facilitate identification of the mutant gene. The closely linked DNA polymorphisms will also provide the means to determine whether other inherited chondrodystrophies have underlying defects in the same gene.     

Resolution of the two loci for autosomal dominant aniridia, AN1 and AN2, to a single locus on chromosome 11p13.

Two distinct loci have been proposed for aniridia; AN1 for autosomal dominant aniridia on chromosome 2p and AN2 for the aniridia in the WAGR contiguous gene syndrome on chromosome 11p13. In this report, the kindred segregating for autosomal dominant aniridia, which suggested linkage to acid phosphatase-1 (ACP1) and led to the assignment of the AN1 locus on chromosome 2p, has been updated and expanded. Linkage analysis between the aniridia phenotype and ACP1 does not support the original linkage results, excluding linkage up to theta = 0.17 with Z = -2. Tests for linkage to other chromosome 2p markers. APOB, D2S71, D2S5, and D2S1, also excluded linkage to aniridia. Markers that have been isolated from the chromosome 11p13 region were then analyzed in this aniridia family. Two RFLPs at the D11S323 locus give significant evidence for linkage. The PvuII polymorphism detected by probe p5S1.6 detects no recombinants, with a maximum lod score of Z = 6.97 at theta = 0.00. The HaeIII polymorphism detected by the probe p5BE1.2 gives a maximum lod score of Z = 2.57 at theta = 0.00. Locus D11S325 gives a lod score of Z = 1.53 at theta = 0.00. These data suggest that a locus for aniridia (AN1) on chromosome 2p has been misassigned and that this autosomal dominant aniridia family is segregating for an aniridia mutation linked to markers in the 11p13 region.     

Autosomal dominant aniridia linked to the chromosome 11p13 markers catalase and D11S151 in a large Dutch family

In a large pedigree with autosomal dominant aniridia, we found close linkage between the aniridia locus AN2 and the markers catalase (CAT) (zeta = 7.27 at theta = 0.00) and D11S151 (zeta = 3.86 at theta = 0.10) flanking the AN2 locus on 11p13. Positive lod scores were also obtained for the 11p13----11p14 markers D11S16 and FSHB with the linkage group CAT/AN2/D11S151. We conclude that the autosomal dominant aniridia in this family is due to a mutation at the AN2 locus on 11p13. We have excluded linkage (zeta less than -2 at theta less than 0.18) between the aniridia and the chromosome 2p25 marker D2S1 (linked to ACP1).     

Epidermolysis bullosa: evidence for linkage to genetic markers on chromosome 1 in a family with the autosomal dominant simplex form

DNA from members of a three-generation pedigree of Irish origin, displaying an autosomal dominant simplex form of epidermolysis bullosa of the epidermolytic, simplex, or Koebner variety (EBS2), was analyzed for linkage with a set of markers derived from the long arm of chromosome 1. Two-point analysis revealed positive lod scores for five of these markers, AT3 (Z = 2.107, theta = 0), APOA2 (Z = 1.939, theta = 0.15), D1S66 (Z = 1.204, theta = 0), D1S13 (Z = 1.026, theta = 0.15), and D1S65 (Z = 0.329, theta = 0.15). Multilocus analysis, incorporating the markers D1S19, D1S16, D1S13, APOA2, D1S66, AT3, and D1S65, resulted in a lod score of 3 maximizing at AT3. These data strongly support previous tentative indications of linkage between EBS2 and genetic markers on the long arm of chromosome 1.     

A new locus on chromosome 12p13.3 for pseudohypoaldosteronism type II, an autosomal dominant form of hypertension

Pseudohypoaldosteronism type II (PHA2) is a rare autosomal dominant form of volume-dependent low-renin hypertension characterized by hyperkalemia and hyperchloremic acidosis but also by a normal glomerular filtration rate. These features, together with the correction of blood pressure and metabolic abnormalities by small doses of thiazide diuretics, suggest a primary renal tubular defect. Two loci have previously been mapped at low resolution to chromosome 1q31-42 (PHA2A) and 17p11-q21 (PHA2B). We have now analyzed a new, large French pedigree, in which 12 affected members over three generations confirmed the autosomal dominant inheritance. Affected subjects had hypertension together with long-term hyperkalemia (range 5.2-6.2 mmol/liter), hyperchloremia (range: 100-109 mmol/liter), normal plasma creatinine (range: 63-129 mmol/liter) and low renin levels. Genetic linkage was excluded for both PHA2A and PHA2B loci (all LOD scores Z<-3.2 at recombination fraction [theta] 0), as well as for the thiazide-sensitive sodium-chloride cotransporter gene. A genome-wide scan using 383 microsatellite markers showed a strong linkage with the chromosome 12p13 region (maximum LOD score Z=6.18, straight theta=0, at D12S99). Haplotype analysis using 10 additional polymorphic markers led to a minimum 13-cM interval flanked by D12S1652 and D12S336, thus defining a new PHA2C locus. Analysis of two obvious candidate genes (SCNN1A and GNb3) located within the interval showed no deleterious mutation. In conclusion, we hereby demonstrate further genetic heterogeneity of this Mendelian form of hypertension and identify a new PHA2C locus, the most compelling and precise linkage interval described to date.     

The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval

Recently, a new locus (PARK8) for autosomal dominant parkinsonism has been identified in one large Japanese family. Linkage has been shown to a 16-cM centromeric region of chromosome 12, between markers D12S1631 and D12S339. We tested 21 white families with Parkinson disease and an inheritance pattern compatible with autosomal dominant transmission for linkage in this region. Criteria for inclusion were at least three affected individuals in more than one generation. A total of 29 markers were used to saturate the candidate region. One hundred sixty-seven family members were tested (84 affected and 83 unaffected). Under the assumption of heterogeneity and through use of an affecteds-only model, a maximum multipoint LOD score of 2.01 was achieved in the total sample, with an estimated proportion of families with linkage of 0.32. This LOD score is significant for linkage in a replication study and corresponds to a P value of.0047. Two families (family A [German Canadian] and family D [from western Nebraska]) reached significant linkage on their own, with a combined maximum multipoint LOD score of 3.33, calculated with an affecteds-only model (family A: LOD score 1.67, P=.0028; family D: LOD score 1.67, P=.0028). When a penetrance-dependent model was calculated, the combined multipoint LOD score achieved was 3.92 (family A: LOD score 1.68, P=.0027; family D: LOD score 2.24, P=.0007). On the basis of the multipoint analysis for the combined families A and D, the 1-LOD support interval suggests that the most likely disease location is between a CA repeat polymorphism on genomic clone AC025253 (44.5 Mb) and marker D12S1701 (47.7 Mb). Our data provide evidence that the PARK8 locus is responsible for the disease in a subset of families of white ancestry with autosomal dominant parkinsonism, suggesting that it could be a more common locus.     

A new locus for generalized epilepsy with febrile seizures plus maps to chromosome 2

Generalized epilepsy with febrile seizures plus (GEFS+) is a recently recognized but relatively common form of inherited childhood-onset epilepsy with heterogeneous epilepsy phenotypes. We genotyped 41 family members, including 21 affected individuals, to localize the gene causing epilepsy in a large family segregating an autosomal dominant form of GEFS+. A genomewide search examining 197 markers identified linkage of GEFS+ to chromosome 2, on the basis of an initial positive LOD score for marker D2S294 (Z=4.4, recombination fraction [straight theta] = 0). A total of 24 markers were tested on chromosome 2q, to define the smallest candidate region for GEFS+. The highest two-point LOD score (Zmax=5.29; straight theta=0) was obtained with marker D2S324. Critical recombination events mapped the GEFS+ gene to a 29-cM region flanked by markers D2S156 and D2S311, with the idiopathic generalized epilepsy locus thereby assigned to chromosome 2q23-q31. The existence of the heterogeneous epilepsy phenotypes in this kindred suggests that seizure predisposition determined by the GEFS+ gene on chromosome 2q could be modified by other genes and/or by environmental factors, to produce the different seizure types observed.     

Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36

Combining data from a genomic screen in 70 families with a high risk for prostate cancer (PC) with data from candidate-region mapping in these families and an additional 71 families, we have localized a potential hereditary PC-susceptibility locus to chromosome 1p36. Because an excess of cases of primary brain cancer (BC) have been observed in some studies of families with a high risk for PC, and because loss of heterozygosity at 1p36 is frequently observed in BC, we further evaluated 12 families with both a history of PC and a blood relative with primary BC. The overall LOD score in these 12 families was 3.22 at a recombination fraction (theta) of .06, with marker D1S507. On the basis of an a priori hypothesis, this group was stratified by age at diagnosis of PC. In the younger age group (mean age at diagnosis <66 years), a maximum two-point LOD score of 3.65 at straight theta = .0 was observed, with D1S407. This linkage was rejected in both early- and late-onset families without a history of BC (LOD scores -7.12 and -6.03, respectively, at straight theta = .0). After exclusion of 3 of the 12 families that had better evidence of linkage to previously described PC-susceptibility loci, linkage to the 1p36 region was suggested by a two-point LOD score of 4.74 at straight theta = .0, with marker D1S407. We conclude that a significant proportion of these families with both a high risk for PC and a family member with BC show linkage to the 1p36 region.     

Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31.

Distal myopathy refers to a heterogeneous group of disorders in which the initial manifestations are weakness and atrophy of the hands and feet. We report a family segregating an autosomal dominant distal myopathy, with multiple affected individuals in whom vocal cord and pharyngeal weakness may accompany the distal myopathy, without involvement of the ocular muscles. To our knowledge, this pedigree displays a distinct distal myopathy with the added features of pharyngeal and vocal cord dysfunction (VCPDM) that has not been previously reported. We mapped the MPD2 gene for VCPDM to chromosome 5q within a 12-cM linkage interval between markers D5S458 and D5S1972 in a large pedigree (a maximum LOD score of 12.94 at a recombination fraction of 0 for D5S393) and combined genome screening and DNA pooling successfully adapted to fluorescent markers. This technique provides for the possibility of fully automated genome scans.     

Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis.

Postaxial polydactyly type-A (PAP-A) in humans is an autosomal dominant trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is well formed and articulates with the fifth, or extra, metacarpal/metatarsal, and thus it is usually functional. In order to map the gene responsible for PAP-A, we studied a five-generation Indian family of 37 individuals (15 of whom were affected). A genomewide search with highly informative polymorphic markers on part of the pedigree showed linkage between the PAP-A phenotype and markers on chromosome 7p15-q11.23 (no crossovers were found with D7S526, D7S795, D7S528, D7S521, D7S691, D7S667, D7S478, D7S1830, D7S803, D7S801, or ELN). The highest LOD score was obtained with marker D7S801 (zeta max = 4.21; theta = 0). Haplotype analysis enabled the mapping of the PAP-A phenotype in this family between markers D7S2848 and D7S669. Analysis of additional families with PAP-A will narrow down the critical genomic region, facilitate positional cloning of the PAP-A gene, and/or uncover potential genetic heterogeneity.     

A novel locus for autosomal dominant nonsyndromic hearing loss (DFNA44) maps to chromosome 3q28–29

Hereditary non-syndromic sensorineural hearing loss (NSSHL) is a genetically highly heterogeneous group of disorders. Autosomal dominant forms account for up to 20% of cases. To date, 39 loci have been identified by linkage analysis of affected families that segregate NSSHL forms in the autosomal dominant mode (DFNA). Investigation of a large Spanish pedigree with autosomal dominant inheritance of bilateral and progressive NSSHL of postlingual onset excluded linkage to known DFNA loci and, in a subsequent genome-wide scan, the disorder locus was mapped to 3q28-29. A maximum two-point LOD score of 4.36 at theta=0 was obtained for marker D3S1601. Haplotype analysis placed the novel locus, DFNA44, within a 3-cM genetic interval defined by markers D3S1314 and D3S2418. Heteroduplex analysis and DNA sequencing of coding regions and exon/intron boundaries of two genes (CLDN16 and FGF12) in this interval did not reveal disease-causing mutations.     

Congenital motor nystagmus linked to Xq26-q27.

Congenital motor nystagmus (CMN) is a hereditary disorder characterized by bilateral ocular oscillations that begin in the first 6 mo of life. It must be distinguished from those genetic disorders-such as ocular albinism (OA), congenital stationary night blindness (CSNB), and blue-cone monochromatism (BCM)-in which nystagmus accompanies a clinically apparent defect in the visual sensory system. Although CMN is presumed to arise from a neurological abnormality of fixation, it is not known whether the molecular defect is located in the eye or in the brain. It may be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern. Three families with CMN inherited in an X-linked, irregularly dominant pattern were investigated with linkage and candidate gene analysis. The penetrance among obligate female carriers was 54%. Evaluation of markers in the region of the genes for X-linked OA, CSNB, and BCM revealed no evidence of linkage, supporting the hypothesis that CMN represents a distinct entity. The gene was mapped to chromosome Xq26-q27 with the following markers: GATA172D05 (LOD score 3.164; recombination fraction [theta] = 0.156), DXS1047 (LOD score 10.296; theta = 0), DXS1192 (LOD score 8.174; theta = 0.027), DXS1232 (LOD score 6.015; theta = 0.036), DXS984 (LOD score 6.695; theta = 0), and GATA31E08 (LOD score 4.940; theta = 0.083). Assessment of haplotypes and multipoint linkage analysis, which gave a maximum LOD score of 10.790 with the 1-LOD-unit support interval spanning approximately 7 cM, place the gene in a region between GATA172D05 and DXS1192. Evaluation of candidate genes CDR1 and SOX3 did not reveal mutations in affected male subjects.     

Hereditary geniospasm: linkage to chromosome 9q13-q21 and evidence for genetic heterogeneity.

Hereditary geniospasm is an unusual movement disorder causing episodes of involuntary tremor of the chin and the lower lip. Episodes typically start in early childhood and may be precipitated by stress, concentration, and emotion. Hereditary geniospasm is inherited as an autosomal dominant trait, and its cause is not known. We report the results of a genomewide genetic linkage study in a four-generation British family with hereditary geniospasm. Positive two-point LOD scores were obtained for 15 microsatellite markers on the peri-centromeric region of chromosome 9. A maximum two-point LOD score of 5.24 at theta = .00 was obtained for the marker D9S1837. Construction of haplotypes defined an interval of 2.1 cM between the flanking markers D9S1806 and D9S175, thus assigning one locus for hereditary geniospasm to the proximal long arm of chromosome 9q13-q21. Hereditary geniospasm in a second British family is not linked to this region, indicating genetic heterogeneity. These findings may have implications for other inherited focal movement disorders that as yet remain unmapped.     

Dominant intermediate Charcot-Marie-Tooth neuropathy maps to chromosome 19p12-p13.2

The hereditary disorders of peripheral nerve form one of the most common groups of human genetic diseases, collectively called Charcot-Marie-Tooth (CMT) neuropathy. Using linkage analysis we have identified a new locus for a form of CMT that we have called "dominant intermediate CMT" (DI-CMT). A genomewide screen using 383 microsatellite markers showed strong linkage to the short arm of chromosome 19 (maximum LOD score 4.3, with a recombination fraction (straight theta) of 0, at D19S221 and maximum LOD score 5.28, straight theta=0, at D19S226). Haplotype analysis performed with 14 additional markers placed the DI-CMT locus within a 16.8-cM region flanked by the markers D19S586 and D19S546. Multipoint linkage analysis suggested the most likely location at D19S226 (maximum multipoint LOD score 6.77), within a 10-cM confidence interval. This study establishes the presence of a locus for DI-CMT on chromosome 19p12-p13.2.