A new locus for autosomal dominant stargardt-like disease maps to chromosome 4

Stargardt disease (STGD) is the most common hereditary macular dystrophy and is characterized by decreased central vision, atrophy of the macula and underlying retinal-pigment epithelium, and frequent presence of prominent flecks in the posterior pole of the retina. STGD is most commonly inherited as an autosomal recessive trait, but many families have been described in which features of the disease are transmitted in an autosomal dominant manner. A recessive locus has been identified on chromosome 1p (STGD1), and dominant loci have been mapped to both chromosome 13q (STGD2) and chromosome 6q (STGD3). In this study, we describe a kindred with an autosomal dominant Stargardt-like phenotype. A genomewide search demonstrated linkage to a locus on chromosome 4p, with a maximum LOD score of 5.12 at a recombination fraction of.00, for marker D4S403. Analysis of extended haplotypes localized the disease gene to an approximately 12-cM interval between loci D4S1582 and D4S2397. Therefore, this kindred establishes a new dominant Stargardt-like locus, STGD4.     

The gene for cherubism maps to chromosome 4p16.3.

Cherubism is a rare familial disease of childhood characterized by proliferative lesions within the mandible and maxilla that lead to prominence of the lower face and an appearance reminiscent of the cherubs portrayed in Renaissance art. Resolution of these bony abnormalities is often observed after puberty. Many cases are inherited in an autosomal dominant fashion, although several cases without a family history have been reported. Using two families with clinically, radiologically, and/or histologically proved cherubism, we have performed a genomewide linkage search and have localized the gene to chromosome 4p16.3, with a maximum multipoint LOD score of 5. 64. Both families showed evidence of linkage to this locus. Critical meiotic recombinants place the gene in a 3-cM interval between D4S127 and 4p-telomere. Within this region a strong candidate is the gene for fibroblast growth factor receptor 3 (FGFR3); mutations in this gene have been implicated in a diverse set of disorders of bone development.     

Haplotype analysis for mucocutaneous venous malformations in a Chinese Han ethnic family

A Chinese Han ethnic family with mucocutaneous venous malformations (VMCM) was investigated. This family has autosomal dominantly inherited VMCM in five generations, and the offspring has a 50% risk of this inherited disorder. Affected individuals have small, spongy, and multiple vascular lesions, which often locate in the skin, oral mucosa, and upper and lower extremities. None of the family members had gastrointestinal bleeding, central nervous system involvement and cardiac defects. Pathological analysis showed that the veins have irregular vascular space and walls with variable thickness. All phenotypes of the patients displayed the basic characters of VMCM. To analyze the genetic locus and haplotype, genomic DNA of 26 family members was obtained from peripheral leukocytes, and the linkage analysis and haplotypes analysis were performed using microsatellites markers. The results of two-point linkage analysis and haplotype analysis showed that the disease-causing gene located within a 7 cM region between D9S1121 and D9S161 on the short arm of chromosome 9. The study firstly reported the Chinese family with VMCM, which disease-causing gene is located in 9p, consistent with western VMCM families reported. Four flanking markers, D9S1121, D9S169, D9S16 and D9S248, were used to define the linkage haplotypes in the family, which can provide useful informaion for researchers to study VMCM in different racial background.     

一个中国汉族皮肤和粘膜多发静脉血管畸形家系的单倍型分析

根据患者的临床体征以及家系的遗传方式,文章对一个中国汉族皮肤和粘膜多发静脉血管畸形(Mucocutaneous venous malformations,VMCM)家系进行了临床诊断。家系中连续5代都有患者,男女患者比例约1:1,为常染色体显性遗传方式。患者皮肤、口腔粘膜、舌头以及四肢等处可见蓝紫色、突出皮面、质硬、压之不褪色的瘤体,组织病理学显示,静脉血管的管腔极不规则,部分管壁存在缺失,部分管壁明显增厚。患者无消化道出血史,无心脏和脑部异常,临床诊断为VMCM。为了进行致病基因的定位和单倍型分析,采集了家族中26人的外周血并提取基因组DNA,并设计微卫星引物进行了连锁和单倍型分析。两点间连锁分析的结果表明,在D9S1121处有最大LOD值为Z=5.38(θ=0.00),单倍型分析的结果提示,致病基因定位于9号染色体短臂上D9S1121和D9S161之间约7 cM的范围内。文章首次报道了中国汉族VMCM家系,其致病基因定位定位于9p,与已报道的欧洲家系相同。用4个微卫星标记D9S1121、D9S 169、D9S161和D9S248确定了该家系致病基因的单倍型,为不同种族和人群VMCM疾病相关研究提供参考。     

Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1.

Benign adult familial myoclonic epilepsy is an autosomal dominant idiopathic epileptic syndrome characterized by adult-onset tremulous finger movement, myoclonus, epileptic seizures, and nonprogressive course. It was recently recognized in Japanese families. In this study, we report that the gene locus is assigned to the distal long arm of chromosome 8, by linkage analysis in a large Japanese kindred with a maximum two-point LOD score of 4.31 for D8S555 at recombination fraction of 0 (maximum multipoint LOD score of 5.42 for the interval between D8S555 and D8S1779). Analyses of recombinations place the locus within an 8-cM interval, between D8S1784 and D8S1694, in which three markers, D8S1830, D8S555, and D8S1779, show no recombination with the phenotypes. Although three other epilepsy-related loci on chromosome 8q have been recognized-one on chromosome 8q13-21 (familial febrile convulsion) and two others on chromosome 8q24 (KCNQ3 and childhood absence epilepsy)-the locus assigned here is distinct from these three epilepsy-related loci. This study establishes the presence of a new epilepsy-related locus on 8q23.3-q24.11.     

Confirmation of chromosome 9p linkage in familial melanoma

Malignant melanoma occurs as a familial cancer in 5%–10% of cases where it segregates in a manner consistent with autosomal dominant inheritance. Evidence from cytogenetics, fine-mapping studies of deletions in melanomas, and recent linkage studies supports the location of a human melanoma predisposition gene on the short arm of chromosome 9. We have carried out linkage analysis using the 9p markers IFNA and D9S126 in 26 Australian melanoma kindreds. Multipoint analysis gave a peak lod score of 4.43, 15 cM centromeric to D9S126, although a lod score of 4.13 was also found 15 cM telomeric of IFNA. These data confirm the existence of a melanoma susceptibility gene on 9p and indicate that this locus most probably lies outside of the IFNA–D9S126 interval. No significant heterogeneity was found between families, when either pairwise or multipoint data were analyzed using HOMOG.     

Fine mapping of the nail-patella syndrome locus at 9q34.

Nail-patella syndrome (NPS), or onychoosteodysplasia, is an autosomal dominant, pleiotropic disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns, and nephropathy. Previous studies have demonstrated linkage of the nail-patella locus to the ABO and adenylate kinase loci on human chromosome 9q34. As a first step toward isolating the NPS gene, we present linkage analysis with 13 polymorphic markers in five families with a total of 69 affected persons. Two-point linkage analysis with the program MLINK showed tight linkage of NPS and the anonymous markers D9S112 (LOD = 27.0; theta = .00) and D9S315 (LOD = 22.0; theta = .00). Informative recombination events place the NPS locus within a 1-2-cM interval between D9S60 and the adenylate kinase gene (AK1).     

Machado Joseph disease is not an allele of the spinocerebellar ataxia 2 locus

Machado Joseph disease (MJD) is a progressive, spinocerebellar ataxia (SCA) with an autosomal dominant mode of inheritance and almost complete penetrance. Clinically, it is difficult to distinguish it from other autosomal dominantly inherited ataxias, and it has been suggested that MJD may be caused by an allelic variant of SCA. Exclusion of MJD from the SCA1 locus on chromosome 6p has previously been demonstrated. However, following the recent assignment of a second locus for spinocerebellar ataxia (SCA2) to chromosome 12q in a large Cuban kindred of Spanish origin, we have investigated linkage in MJD families using the two markers, D12S58 and PLA2, that flank this disease gene. The MJD locus was definitively excluded from an interval spanning approximately 70 cM, which includes these loci. These studies demonstrate that MJD and SCA2 are genetically distinct despite similarities in disease phenotype and ancestral origins of the patients. Thus, the as yet unmapped MJD locus represents a third SCA locus, providing further evidence for genetic heterogeneity within these disorders.     

Identification of a new autosomal dominant limb-girdle muscular dystrophy locus on chromosome 7.

We report the identification of a new locus for autosomal dominant limb-girdle muscular dystrophy (LGMD1) on 7q. Two of five families (1047 and 1701) demonstrate evidence in favor of linkage to this region. The maximum two-point LOD score for family 1047 was 3.76 for D7S427, and that for family 1701 was 2.63 for D7S3058. Flanking markers place the LGMD1 locus between D7S2423 and D7S427, with multipoint analysis slightly favoring the 9-cM interval spanned by D7S2546 and D7S2423. Three of five families appear to be unlinked to this new locus on chromosome 7, thus establishing further heterogeneity within the LGMD1 diagnostic classification.     

Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q.

Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. The neuronal form of this disorder is referred to as Charcot-Marie-Tooth type II disease (CMT2). CMT2 is usually inherited as an autosomal dominant trait with a variable age at onset of symptoms associated with progressive axonal neuropathy. In some families, the locus that predisposes to CMT2 has been demonstrated to map to the distal portion of the short arm of chromosome 1. Other families with CMT2 do not show linkage with 1p markers, suggesting genetic heterogeneity in CMT2. We investigated linkage in a single large kindred with autosomal dominant CMT2. The gene responsible for CMT2 in this kindred (CMT2B) was mapped to the interval between the microsatellite markers D3S1769 and D3S1744 in the 3q13-22 region. Study of additional CMT2 kindreds should serve to further refine the disease gene region and may ultimately lead to the identification of a gene defect that underlies the CMT2 phenotype.     

An autosomal recessive nonsyndromic-hearing-loss locus identified by DNA pooling using two inbred Bedouin kindreds.

Autosomal recessive nonsyndromic hearing loss (ARNSHL) is the most common form of severe inherited childhood deafness. We present the linkage analysis of two inbred Bedouin kindreds from Israel that are affected with ARNSHL. A rapid genomewide screen for markers linked to the disease was performed by using pooled DNA samples. This screen revealed evidence for linkage with markers D9S922 and D9S301 on chromosome 9q. Genotyping of individuals from both kindreds confirmed linkage to chromosome 9q and a maximum combined LOD score of 26.2 (recombination fraction [theta] .025) with marker D9S927. The disease locus was mapped to a 1.6-cM region of chromosome 9ql3-q2l, between markers D9S15 and D9S927. The disease segregates with a common haplotype in the two kindreds, at markers D9S927, D9S175, and D9S284 in the linked interval, supporting the hypothesis that both kindreds inherited the deafness gene from a common ancestor. Although this nonsyndromic-hearing-loss (NSHL) locus maps to the same cytogenetic interval as DFNB7, it does not overlap the currently defined DFNB7 interval and may represent (1) a novel form of NSHL in close proximity to DFNB7 or (2) a relocalization of the DFNB7 interval to a region telomeric to its reported location. This study further demonstrates that DNA pooling is an effective means of quickly identifying regions of linkage in inbred families with heterogeneous autosomal recessive disorders.     

A Bedouin kindred with infantile nephronophthisis demonstrates linkage to chromosome 9 by homozygosity mapping.

A novel type of infantile nephronophthisis was identified in an extended Bedouin family from Israel. This disease has an autosomal recessive mode of inheritance, with the phenotypic presentation ranging from a Potter-like syndrome to hyperechogenic kidneys, renal insufficiency, hypertension, and hyperkalemia. Affected individuals show rapid deterioration of kidney function, leading to end-stage renal failure within 3 years. Histopathologic examination of renal tissue revealed variable findings, ranging from infantile polycystic kidneys to chronic tubulointerstitial nephritis, fibrosis, and cortical microcysts. A known familial juvenile nephronophthisis locus on chromosome 2q13 and autosomal recessive polycystic kidney disease on chromosome 6p21.1-p12 were excluded by genetic linkage analysis. A genomewide screen for linkage was conducted by searching for a locus inherited by descent in all affected individuals. Pooled DNA samples from parents and unaffected siblings and individual DNA samples from four affected individuals were used as PCR templates with trinucleotide- and tetranucleotide-repeat polymorphic markers. Using this approach, we identified linkage to infantile nephronophthisis for markers on chromosome 9q22-31. The disorder maps to a 12.9-cM region flanked by markers D9S280 and GGAT3G09.     

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.     

Localization of the Homolog of a Mouse Craniofacial Mutant to Human Chromosome 18q11 and Evaluation of Linkage to Human CLP and CPO

The transgene-induced mutation 9257 and the spontaneous mutation twirler cause craniofacial and inner ear malformations and are located on mouse chromosome 18 near the ataxia locusax.To map the human homolog of 9257, a probe from the transgene insertion site was used to screen a human genomic library. Analysis of a cross-hybridizing human clone identified a 3-kb conserved sequence block that does not appear to contain protein coding sequence. Analysis of somatic cell hybrid panels assigned the human locus to 18q11. The polymorphic microsatellite markers D18S1001 and D18S1002 were isolated from the human locus and mapped by linkage analysis using the CEPH pedigrees. The 9257 locus maps close to the centromeres of human chromosome 18q and mouse chromosome 18 at the proximal end of a conserved linkage group. To evaluate the role of this locus in human craniofacial disorders, linkage to D18S1002 was tested in 11 families with autosomal dominant nonsyndromic cleft lip and palate and 3 families with autosomal dominant cleft palate only. Obligatory recombinants were observed in 8 of the families, and negative lod scores from the other families indicated that these disorders are not linked to the chromosome 18 loci.     

Molecular genetic analysis of essential tremor

Essential tremor (ET) is the most common extrapyramidal disorder of the central nervous system with autosomal dominant transmission in the majority of cases and age-dependent penetrance of the mutant gene. In a number of cases, it shares some phenotypic features with autosomal dominant idiopathic torsion dystonia (locus DYT1 on chromosome 9q32-34) and is genetically heterogeneous: distinct variants of ET were mapped to chromosomes 3q13 (ETM1) and 2p22-25 (ETM2). We performed studies of candidate loci in a group of Slavonic (11 patients) and Tajik (19 patients) families with ET. Mutational analysis of the DYT gene in probands did not reveal the major deletion 946-948delGAG characteristic of idiopathic torsion dystonia, which allows one to genetically distinguish the studied hereditary forms of ET and torsion dystonia. Based on analysis of genetic linkage in informative Tajik pedigrees with ET, linkage to locus ETM1 on chromosome 3q13 was established in four families. Maximum pairwise Lod score was 2.46 at recombination fraction of theta = 0.00; maximum combined multipoint Lod score was 3.35 for marker D3S3720 and a common "mutant" haplotype for markers D3S3620, D3S3576, and D3S3720 allowed us to locate a mutant gene in a relatively narrow chromosome region spanning 2 cM. In one informative pedigree with ET, both candidate loci ETM1 and ETM2 were definitely excluded on the basis of negative Lod scores obtained by linkage estimations, which testifies to the existence of another distinct gene for autosomal dominant ET.     

Refinement of the locus for autosomal dominant hereditary gingival fibromatosis (GINGF) to a 3.8-cM region on 2p21

Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease characterized by enlargement of gingiva. Recently, a locus for autosomal dominant HGF has been mapped to an 11-cM region on chromosome 2p21. In the current investigation, we genotyped four Chinese HGF families using polymorphic microsatellite markers on 2p21. The HOMOG test provided evidence for genetic homogeneity, with evidence for linkage in four families (heterogeneity versus homogeneity test HOMOG, chi(2) = 0. 00). A cumulative maximum two-point lod score of 5.04 was produced with marker D2S390 at a recombination frequency of θ = 0 in the four linked families. Haplotype analysis localized the hereditary gingival fibromatosis locus within the region defined by D2S352 and D2S2163. This region overlaps by 3.8 cM with the previously reported HGF region. Single-strand conformation polymorphism and sequence analysis of the coding region of cytochrome P450 1B1 (CYP1B1) excluded it as a likely candidate gene.     

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.