A second locus for familial high myopia maps to chromosome 12q.

Myopia, or nearsightedness, is the most common eye disorder worldwide. "Pathologic" high myopia, or myopia of <=-6.00 diopters, predisposes individuals to retinal detachment, macular degeneration, cataract, or glaucoma. A locus for autosomal dominant pathologic high myopia has been mapped to 18p11.31. We now report significant linkage of high myopia to a second locus at the 12q21-23 region in a large German/Italian family. The family had no clinical evidence of connective-tissue abnormalities or glaucoma. The average age at diagnosis of myopia was 5.9 years. The average spherical-component refractive error for the affected individuals was -9.47 diopters. Markers flanking or intragenic to the genes for the 18p locus, Stickler syndromes type I and II (12q13.1-q13.3 and 6p21.3), Marfan syndrome (15q21.1), and juvenile glaucoma (chromosome 1q21-q31) showed no linkage to the myopia in this family. The maximum LOD score with two-point linkage analysis in this pedigree was 3.85 at a recombination fraction of .0010, for markers D12S1706 and D12S327. Recombination events identified markers D12S1684 and D12S1605 as flanking markers that define a 30.1-cM interval on chromosome 12q21-23, for the second myopia gene. These results confirm genetic heterogeneity of myopia. The identification of this gene may provide insight into the pathophysiology of myopia and eye development.     

Localization of the fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to the 10p15-p14 region.

One of the major causes of blindness is primary open-angle glaucoma, which affects millions of elderly people worldwide. Genetic studies have so far mapped three loci for the adult-onset form of this condition to the 2cen-q13, 3q21-q24, and 8q23 regions. Herein, we report the localization of a fourth locus, to the 10p15-p14 region, in one large British family with a classical form of normal-tension open-angle glaucoma. Of the 42 meioses genotyped in this pedigree, 39 subjects (16 affected) inherited a haplotype compatible with their prior clinical designation, whereas the remaining 3 were classified as unknown. Although a maximum LOD score of 10.00 at a recombination fraction of straight theta=.00 was obtained with D10S1216, 21 other markers provided significant values, varying between 3.77 and 9.70. When only the affected meioses of this kindred were analyzed, LOD scores remained statistically significant, ranging from 3.16 (D10S527) to 3.57 (D10S506). Two critical recombinational events in the affected subjects positioned this new locus to a region of approximately 21 cM, flanked by D10S1729 and D10S1664. However, an additional recombination in a 59-year-old unaffected female suggests that this locus resides between D10S585 (or D10S1172) and D10S1664, within a genetic distance of 5-11 cM. However, the latter minimum region must be taken cautiously, because the incomplete penetrance has previously been documented for this group of eye conditions. A partial list of genes that positionally are considered as candidates includes NET1, PRKCT, ITIH2, IL2RA, IL15RA, IT1H2, hGATA3, the mRNA for open reading frame KIAA0019, and the gene for D123 protein.     

Evidence that a locus for familial high myopia maps to chromosome 18p.

Myopia, or nearsightedness, is the most common human eye disorder. A genomewide screen was conducted to map the gene(s) associated with high, early-onset, autosomal dominant myopia. Eight families that each included two or more individuals with >=-6.00 diopters (D) myopia, in two or more successive generations, were identified. Myopic individuals had no clinical evidence of connective-tissue abnormalities, and the average age at diagnosis of myopia was 6.8 years. The average spherical component refractive error for the affected individuals was -9.48 D. The families contained 82 individuals; of these, DNA was available for 71 (37 affected). Markers flanking or intragenic to the genes for Stickler syndrome types 1 and 2 (chromosomes 12q13.1-q13.3 and 6p21.3, respectively), Marfan syndrome (chromosome 15q21.1), and juvenile glaucoma (chromosome 1q21-q31) were also analyzed. No evidence of linkage was found for markers for the Stickler syndrome types 1 and 2, the Marfan syndrome, or the juvenile glaucoma loci. After a genomewide search, evidence of significant linkage was found on chromosome 18p. The maximum LOD score was 9.59, with marker D18S481, at a recombination fraction of .0010. Haplotype analysis further refined this myopia locus to a 7.6-cM interval between markers D18S59 and D18S1138 on 18p11.31.     

A locus for autosomal dominant colobomatous microphthalmia maps to chromosome 15q12-q15

Congenital microphthalmia is a common developmental ocular disorder characterized by shortened axial length. Isolated microphthalmia is clinically and genetically heterogeneous and may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Here, we studied a five-generation family of Sephardic Jewish origin that included 38 members, of whom 7 have either unilateral or bilateral microphthalmia of variable severity inherited as an autosomal dominant trait with incomplete penetrance. After exclusion of several candidate loci, we performed a genome-scan study and demonstrated linkage to chromosome 15q12-q15. Positive LOD scores were obtained with a maximum at the D15S1007 locus (maximum LOD score 3.77, at recombination fraction 0.00). Haplotype analyses supported the location of the disease-causing gene in a 13.8-cM interval between loci D15S1002 and D15S1040.     

Familial Chordoma, a Tumor of Notochordal Remnants, Is Linked to Chromosome 7q33

Chordoma is a rare tumor originating from notochordal remnants that is usually diagnosed during midlife. We performed a genomewide analysis for linkage in a family with 10 individuals affected by chordoma. The maximum two-point LOD score based on only the affected individuals was 2.21, at recombination fraction 0, at marker D7S2195 on chromosome 7q. Combined analysis of additional members of this family (11 affected individuals) and of two unrelated families (one with 2 affected individuals and the other with 3 affected individuals), with 20 markers on 7q, showed a maximum two-point LOD score of 4.05 at marker D7S500. Multipoint analysis based on only the affected individuals gave a maximum LOD score of 4.78, with an approximate 2-LOD support interval from marker D7S512 to marker D7S684. Haplotype analysis of the three families showed a minimal disease-gene region from D7S512 to D7S684, a distance of 11.1 cM and approximately 7.1 Mb. No loss of heterozygosity was found at markers D7S1804, D7S1824, and D7S2195 in four tumor samples from affected family members. These results map a locus for familial chordoma to 7q33. Further analysis of this region, to identify this gene, is ongoing.     

Familial glaucoma iridogoniodysplasia maps to a 6p25 region implicated in primary congenital glaucoma and iridogoniodysgenesis anomaly.

Familial glaucoma iridogoniodysplasia (FGI) is a form of open-angle glaucoma in which developmental anomalies of the iris and irido-corneal angle are associated with a juvenile-onset glaucoma transmitted as an autosomal dominant trait. A single large family with this disorder was examined for genetic linkage to microsatellite markers. A peak LOD score of 11.63 at a recombination fraction of 0 was obtained with marker D6S967 mapping to chromosome 6p25. Haplotype analysis places the disease gene in a 6.4-cM interval between the markers D6S1713 and D6S1600. Two novel clinical appearances extend the phenotypic range and provide evidence of variable expressivity. The chromosome 6p25 region is now implicated in FGI, primary congenital glaucoma, and iridogoniodysgenesis anomaly. This may indicate the presence of a common causative gene or, alternatively, a cluster of genes involved in eye development/function.     

Identification of a New Locus for Generalized Epilepsy with Febrile Seizures Plus (GEFS+) on Chromosome 2q24-q33

We report the identification of a new locus for generalized epilepsy with febrile seizures plus (GEFS+). Six family members manifested isolated typical febrile seizures (FS), and five had typical FS associated with generalized epilepsy (FS+, generalized tonic/clonic seizures). Afebrile seizures occurred from childhood until the teenage years. The maximum two-point LOD score was 3.99 for markers D2S294 and D2S2314. Flanking markers place the GEFS+ locus between D2S141 and D2S116, with multipoint analysis favoring the 13-cM interval spanned by D2S294 and D2S364. This locus is the second GEFS+ locus to be reported, which suggests that this syndrome is genetically heterogeneous.     

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.     

Localization of a novel gene for congenital nonsyndromic simple microphthalmia to chromosome 2q11-14

Microphthalmia is a clinically and genetically heterogeneous disorder of eye development. The genetic basis of nonsyndromic microphthalmia is not yet fully understood. Previous studies indicated that disease pedigrees from different genetic backgrounds could be attributed to completely different gene loci. To investigate the etiology in a large autosomal-dominant inherited simple microphthalmia (nanophthalmia) pedigree, which is the first genetically analyzed Chinese microphthalmia pedigree, we performed a whole-genome scan using 382 micro-satellite DNA markers after the exclusion of reported candidates associated with microphthalmia. Strong evidence indicated that microphthalmia in this family was mapped to an unreported new locus on chromosome 2q. A significantly positive two-point LOD score was obtained with a maximum 3.290 at a recombination fraction of 0.00 for marker D2S2265. Subsequent haplotype analysis and recombination data further confined the disease-causing gene to a 15-cM interval between D2S1890 and D2S347 on 2q11-14. Our results further underlined the degree of heterogeneity in microphthalmia from Chinese background and localized a novel gene which regulates eye embryogenesis.     

The novel genetic disorder microhydranencephaly maps to chromosome 16p13.3-12.1

We studied a large consanguineous Anatolian family with children who exhibited hydranencephaly associated with microcephaly. The children were severely affected. This novel genetic disorder is autosomal recessive. We used autozygosity mapping to identify a locus at chromosome 16p13.3-12.1; it has a LOD score of 4.11. The gene locus is within a maximal 11-cM interval between markers D16S497 and D16S672 and within a minimal critical region of 8 cM between markers D16S748 and D16S490.     

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 novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21-q22 in a Swiss German kindred

DFNA23, a novel locus for autosomal dominant nonsyndromic hearing loss, was identified in a Swiss German kindred. DNA samples were obtained from 22 family members in three generations: 10 with hearing impairment caused by the DFNA23 locus, 8 unaffected offspring, and 4 spouses of hearing-impaired pedigree members. In this kindred, the hearing-impaired family members have prelingual bilateral symmetrical hearing loss. All audiograms from hearing-impaired individuals displayed sloping curves, with hearing ability ranging from normal hearing to mild hearing loss in low frequencies, normal hearing to profound hearing loss in mid frequencies, and moderate to profound hearing loss in high frequencies. A conductive component existed for 50% of the hearing-impaired family members. The majority of the hearing-impaired family members did not display progression of hearing loss. The DFNA23 locus maps to 14q21-q22. Linkage analysis was carried out under a fully penetrant autosomal dominant mode of inheritance with no phenocopies. A maximum multipoint LOD score of 5.1 occurred at Marker D14S290. The 3.0-LOD unit support interval is 9.4 cM and ranged from marker D14S980 to marker D14S1046.     

A gene for autosomal dominant nonsyndromic hearing loss (DFNA12) maps to chromosome 11q22-24.

We performed linkage analysis in a Belgian family with autosomal dominant midfrequency hearing loss, which has a prelingual onset and a nonprogressive course in most patients. We found LOD scores >6 with markers on chromosome 11q. Analysis of key recombinants maps this deafness gene (DFNA12) to a 36-cM interval on chromosome 11q22-24, between markers D11S4120 and D11S912. The critical regions for the recessive deafness locus DFNB2 and the dominant locus DFNA11, which were previously localized to the long arm of chromosome 11, do not overlap with the candidate interval of DFNA12.     

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.     

Dominant hereditary inclusion-body myopathy gene (IBM3) maps to chromosome region 17p13.1

We recently described an autosomal dominant inclusion-body myopathy characterized by congenital joint contractures, external ophthalmoplegia, and predominantly proximal muscle weakness. A whole-genome scan, performed with 161 polymorphic markers and with DNA from 40 members of one family, indicated strong linkage for markers on chromosome 17p. After analyses with additional markers in the region and with DNA from eight additional family members, a maximum LOD score (Zmax) was detected for marker D17S1303 (Zmax=7.38; recombination fraction (theta)=0). Haplotype analyses showed that the locus (Genome Database locus name: IBM3) is flanked distally by marker D17S945 and proximally by marker D17S969. The positions of cytogenetically localized flanking markers suggest that the location of the IBM3 gene is in chromosome region 17p13.1. Radiation hybrid mapping showed that IBM3 is located in a 2-Mb chromosomal region and that the myosin heavy-chain (MHC) gene cluster, consisting of at least six genes, co-localizes to the same region. This localization raises the possibility that one of the MHC genes clustered in this region may be involved in this disorder.     

A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q.

Primary open-angle glaucoma (POAG), which causes progressive loss of the visual fields, was subdivided into two groups according to age at onset: (1) chronic open-angle glaucoma (COAG) diagnosed after age 40 years and (2) juvenile open-angle glaucoma (JOAG) diagnosed between 3 years of age and early adulthood. A JOAG gene (GLC1A) was recently mapped to chromosome 1q. We studied 142 members of a huge multigenerational French Canadian family affected with autosomal dominant POAG. Either JOAG or COAG was diagnosed in 40 patients. Six subjects were also diagnosed with ocular hypertension (OHT), which may lead to POAG. To localize a common disease gene that might be responsible for both glaucoma subsets, we performed linkage analysis considering JOAG and COAG under the same phenotypic category. JOAG/COAG was tightly linked to seven microsatellite markers on chromosome 1q23-q25; a maximum lod score of 6.62 was obtained with AF-M278ye5. To refine the disease locus, we exploited a recombination mapping strategy based on a unique founder effect. The same characteristic haplotype, composed of 14 markers spanning 12 cM between loci D1S196 and D1S212, was recognized in all persons affected by JOAG, COAG, or OHT, but it did not occur in unaffected spouses and in normal family members > 35 years of age, except for three obligatory carriers. Key recombination events confined the disease region within a 9-cM interval between loci D1S445 and D1S416/D1S480. These observations demonstrate that the GLC1A gene is responsible for both adult-onset and juvenile glaucomas and suggest that the JOAG and COAG categories within this family may be part of a clinical continuum artificially divided at age 40 years.     

Confirmation of linkage to 1q21-31 in a Danish autosomal dominant juvenile-onset glaucoma family and evidence of genetic heterogeneity

Autosomal dominant juvenile-onset open-angle glaucoma has been mapped to 1q21-31 in a number of American families. Our study confirms linkage in a Danish five-generation dominant juvenile-onset glaucoma family with a maximum two-point lod score of 6.67 at the D1S210 locus. Multipoint linkage analysis in a nine-generation Swedish family with dominant juvenile-onset glaucoma and iris hypoplasia excludes linkage to the region of approximately 18 cM between loci D1S104 and D1S218, shown to contain the previously mapped glaucoma gene. This study thus provides support for genetic heterogeneity with respect to dominant juvenile-onset glaucoma.     

A locus for autosomal dominant accessory auricular anomaly maps to 14q11.2–q12

Accessory auricular anomaly is a small excrescence of skin that contains elastic cartilage on different regions of the helix and the face. Previous work has shown that the genetic trait of some patients with the isolated symptom of accessory auricular anomaly is autosomal dominant. To map the gene for autosomal dominant accessory auricular anomaly (ADAAA), we investigated a Chinese family with 11 affected individuals. We performed linkage analysis with microsatellite markers spanning the whole human-genome in the family. The inheritance pattern of the ADAAA family was autosomal dominant with complete penetrance. Two-point linkage analysis revealed significant maximum LOD scores of 4.20(D14S990 and D14S264, sita = 0) in the family. Haplotype construction and multipoint linkage analysis also confirmed the locus and defined the isolated ADAAA locus to a 9.84 cM interval between the markers D14S283 and D14S297. Our study assigned an isolated ADAAA locus to 14q11.2–q12. This is the first ADAAA locus reported to date.Y. Yang and J. Guo contribute to this work equally.     

Evidence for linkage of human primary systemic carnitine deficiency with D5S436: a novel gene locus on chromosome 5q.

Primary systemic carnitine deficiency (SCD) is a rare hereditary disorder transmitted by an autosomal recessive mode of inheritance. The disorder includes cardiomyopathy, muscle weakness, hypoketotic coma with hypoglycemia, and hyperammonemia. In this study, we conducted a linkage analysis of a Japanese SCD family with a proband-a 9-year-old girl-and 26 members. The serum and urinary carnitine levels were determined for all members. The entire genome was searched for linkage to the gene locus for SCD, by use of a total of approximately 300 polymorphic markers located approximately 15-20 cM apart. In the family, there were two significantly different phenotypes, in terms of serum free-carnitine levels: low serum free-carnitine level (29.5+/-5.0 microM; n=14) and normal serum free-carnitine level (46.8+/-6.2 microM; n=12). There was no correlation of urinary free-carnitine levels with the low serum-level phenotype (putative heterozygote), but in normal phenotypes (wild type) urinary levels decreased as the serum levels decreased; renal resorption of free carnitine appeared to be complete in wild-type individuals, when the serum free-carnitine level was <36 microM. Linkage analysis using an autosomal dominant mode of inheritance of heterozygosity revealed a tight linkage between the disease allele and D5S436 on chromosome 5q, with a two-point LOD score of 4.98 and a multipoint LOD score of 5.52. The haplotype analysis revealed that the responsible genetic locus lies between D5S658 and D5S434, which we named the "SCD" locus. This region was syntenic with the jvs locus, which is responsible for murine SCD. Phylogenic conversion of the SCD locus strongly suggests involvement of a single gene, in human SCD.     

Linkage analysis of the human dopamine beta-hydroxylase gene

The human gene for dopamine beta-hydroxylase (D beta H) has been mapped to chromosome 9q34. Using polymerase chain reaction amplification of exon 11 of the D beta H gene followed by digestion of the reaction products with FnuDII (BstUI), we detected a low-frequency restriction fragment length polymorphism (RFLP). The CEPH panel of family DNAs was genotyped for this RFLP, enabling us to determine the linkage relationships between D beta H and four other loci previously mapped to human chromosome 9q. We obtained two-point recombination frequencies (theta) between D beta H and arginosuccinate synthetase (theta = 0, LOD = 7.37), the ABO blood group locus (theta = 0, LOD = 4.5), CRI-P111 (theta = 0, LOD = 2.1), and D9S31 (theta = .06, LOD = 2.81).