Localization of a gene for oculodentodigital syndrome to human chromosome 6q22-q24

Oculodentodigital syndrome (ODD) is a congenital, autosomal dominant disorder which affects the development of the face, eyes, limbs and dentition. Spastic paraparesis is thought to be an occasional manifestation of the disorder. Type III syndactyly, which occurs as part of ODD, has also been reported to occur as an isolated entity. In the current investigation, a total genome search for the location of the ODD locus was instigated and linkage to polymorphic markers located on chromosome 6q established (pairwise Zmax = 9.37; theta = 0.001). Analysis of a large family with type III syndactyly, but atypical facial features, further suggested that isolated type III syndactyly is also located in this same region of the genome.      

The gene for Darier's disease maps to chromosome 12q23-q24.1

Darler's disease is a rare autosomal dominant skin disorderin which there is abnormal adhesion between keratlnocytes. Itappears to be associated with an Increased prevalence of neuropsychiatrlcdisorders including mental retardation and epilepsy. In additionwe have previously reported a family in which major affectivedisorder cosegregates with Darier's disease. In the presentstudy we have localized the gene for Darier's disease to chromosome12q23–q24.1 by linkage analysis in five British pedigrees.We obtained a maximum two point lod score of 4.29 with markerD12S84 at zero recombination fraction. All five families showedevidence of linkage between the disease gene and markers Inthis region. Subsequent identification of the Darier's diseasegene will provide Insights into normal mechanisms of cell adhesionand may be of importance in the genetic Investigation of neuropsychiatricdisorders as well as elucidating the pathogenesls of Darier'sdisease itself.     

The gene for arrhythmogenic right ventricular cardiomyopathy maps to chromosome 14q23-q24

Arrhythmogenic right ventricular cardiomyopathy/dys-plasia (ARVD)is a dominantly inherited disorder progressively affecting themyocardium and it is one of the major causes of juvenile suddendeath. The chromosomal localization of the disease gene is reportedhere for the first time. A maximum lod score of 6.04 was obtainedat      

Assignment of the possible HTLV receptor gene to chromosome 17q21-q23

We have determined the HTLV (Human T-cell leukemia virus) receptor localization more precisely on the human chromosome 17. Based on the fact that HTLV infection induces syncytium formation of infected cells as a result of interaction between the viral envelope and viral receptor, we performed the sensitive biological assay using recombinant vaccinia expression system. Our results from the induced syncytium pattern of the somatic hybrid cell lines with different deletions indicated that the HTLV receptor gene may reside from q21 to q23 on the long arm of the human chromosome 17.     

Linkage disequilibrium mapping of the gene for Hermansky-Pudlak syndrome to chromosome 10q23. 1-q23.3

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disordercharacterized by the triad of tyrosinase-positive oculocutaneousalbinism, bleeding diathesis due to storage-pool deficiencyof platelets, and a lysosomal ceroid storage disease. The disorderis particularly frequent in Puerto Rico and in an isolated villagein the Swiss Alps. We have used a linkage disequilibrium mappingapproach to localize the HPS gene in both of these groups toa 0.6 centiMorgan interval in chromosome segment 10q23.1-q23.3.These results indicate that the Puerto Rican and Swiss formsof HPS are either allelic or that they result from mutationsin very closely linked genes in this region. This region ofdistal chromosome 10q is syntenic to the region of mouse chromosome19 that includes ‘pale ear’ (ep) and ‘ruby-eye’(ru), which must be considered as potential murine homologuesto human HPS.     

A novel locus for parietal foramina maps to chromosome 4q21-q23

Parietal foramina [PFM], inherited usually in an autosomal dominant mode, is an extremely rare developmental defect characterized by a symmetrical, oval hole in the parietal bone. It can be present as either an isolated or a syndromic feature. PFM types 1 and 2 (PFM1 and PFM2) have been found to be caused by mutations in the MSX2 and ALX4 genes, located to chromosomes 5 and 11, respectively. After exclusion of both the above loci in a large Chinese pedigree with autosomal dominant PFM, a genome-wide search revealed a linkage of the PFM to markers at the 4q21-q23 region. The maximum LOD score from two-point linkage analysis is 3.87 for marker D4S2961. Analysis of co-segregated haplotype localized the region to a 20-cM interval that flanks D4S392 and D4S2945. Therefore, we concluded that the PFM in the family is a new PFM locus. Although three genes, BMPR1B, PP1 and IBSP, are located to 4q21-q25 and their functions are related to bone morphogenesis, no mutations were identified by sequencing analysis of their exons.     

Further evidence for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23

Fryns JP, Strømme P, van den Berghe H. Further evidence for the location of the blepharophimosis syndrome (BPES) at 3q22.3-q23.
Clin Genet 1993: 44: 149–151. © Munksgaard, 1993
We report a 6-year-old, mentally retarded boy with typical clinical signs and symptoms of the blepharophimosis syndrome ( b lepharophimosis, p tosis, e picanthus inversus s yndrome (BPES)), born to normal parents. Chromosome studies revealed an interstitial deletion in the long arm of chromosome 3: del(3)(q22.3—q23). This observation reinforces previous suggestions that the location of the BPES gene is at 3q2, i.e. 3q22.3-q23.     

Analysis of a 1-megabase deletion in 15q22-q23 in an autistic patient: identification of candidate genes for autism and of homologous DNA segments in 15q22-q23 and 15q11-q13

We have identified a one megabase deletion in the 15q22-15q23 region in a patient with autism, developmental delay, and mild dysmorphism. Genes that map within the deletion region and genes that are interrupted or rearranged at the deletion breakpoints are candidate genes for autism. Fluroescence in situ hybridization studies in this patient revealed that part or all of the PML gene is absent from one chromosome 15 and a BAC clone containing the D15S124 gene locus hybridizes to only one chromosome 15. BAC clones containing the PTPN9, and SLP-1[hUNC24] genes showed markedly reduced hybridization in the 15q22-q23 region on one chromosome 15 in the patient. These BACs also hybridize to the 15q11-q13 region in close proximity to SNRPN and HERC2, and in this region there is equal intensity of signal on the normal and on the deleted chromosome. There are previous reports of deletions and duplications of the 15q11-q13 region in patients with autism. Our patient represents the first report of a 15q22-q23 deletion. Hybridization of the PTPN9 and Slp-1 Bac clones to the 15q11-q13 and the 15q22-q23 regions of chromosome 15 may be due to the presence of PTPN9 or SLP-1 gene sequences or to the presence of other gene sequences or to non-coding homologous DNA sequences. The PTPN9 gene encodes a non-receptor protein tyrosine phosphatase. The Slp-1 [hUNC24] gene is expressed mainly in the brain. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:765-770, 2000.     

Significant evidence for linkage of febrile seizures to chromosome 5q14-q15

Febrile seizures (FSs) represent the most common form of childhood seizure. In the Japanese population, the incidence rate is as high as 7%. It has been recognized that there is a significant genetic component for susceptibility to this type of seizure. Two putative FS loci, FEB1 (chromosome 8q13-q21) and FEB2 (chromosome 19p), have been mapped. Furthermore, a mutation in the voltage-gated sodium (Na(+))-channel beta1 subunit gene ( SCN1B ) at chromosome 19q13.1 was identified in a family with a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS(+)). These loci are linked to some large families. In this study, we conducted a genome-wide linkage search for FS in one large family with subsequent linkage confirmation in 39 nuclear families. Significant linkage was found at D5S644 by multipoint non-parametric analysis using GENEHUNTER ( P = 5.4 x 10(-6)). Estimated lambda(s)at D5S644 was 2.5 according to maximum likelihood analysis. Significant linkage disequilibria with FS were observed at the markers D5S644, D5S652 and D5S2079 in 47 families by transmission disequilibrium tests. These findings indicate that there is a gene on chromosome 5q14-q15 that confers susceptibility to FSs and we call this gene FEB4.     

A gene for ulnar-mammary syndrome maps to 1 2q23-q24.1

Uinar–mammary syndrome (UMS) is an autosomal dominantdisorder characterized by posterior limb deficiencies or duplications,apocrine/mammary gland hypoplasla and/or dysfunction, abnormaldentition, delayed puberty and genital anomalies. We reportthe mapping of a gene causing UMS to chromosome 1 2q23–24.1.Linkage analysis generated a positive lod score of 6.21 at     

Human gene coding for granulocyte-colony stimulating factor is assigned to the q21-q22 region of chromosome 17

Granulocyte-colony stimulating factor (G-CSF) is a member of colony stimulating factors which regulate the proliferation and differentiation of hematopoietic progenitor cells. A full-length cDNA clone coding human G-CSF was used as a hybridization probe to detect homologous sequence in human-mouse somatic cell hybrids, flow-sorted human chromosomes, and in situ human metaphase chromosomes. The results indicate that the gene encoding human G-CSF is on the q21–q22 region of chromosome 17, which is involved in translocation of t(15;17) (q23;21) in human acutepromyelocytic leukemia.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

Localisation of a gene for transient neonatal diabetes mellitus to an 18.72 cR3000 (approximately 5.4 Mb) interval on chromosome 6q

Transient neonatal diabetes mellitus (TNDM) is a rare condition which presents with intrauterine growth retardation, dehydration, and failure to thrive. The condition spontaneously resolves before 1 year of age but predisposes patients to type 2 diabetes later in life. We have previously shown that, in some cases, TNDM is associated with paternal uniparental disomy (UPD) of chromosome 6 and suggested that an imprinted gene responsible for TNDM lies within a region of chromosome 6q. By analysing three families, two with duplications (family A and patient C) and one with several affected subjects with normal karyotypes (family B), we have further defined the TNDM critical region. In patient A, polymorphic microsatellite repeat analysis identified a duplicated region of chromosome 6, flanked by markers D6S472 and D6S311. This region was identified on the Sanger Centre's chromosome 6 radiation hybrid map (http://www.sanger.ac.uk/HGP/Chr6) and spanned approximately 60 cR3000. Using markers within the region, 418 unique P1 derived artificial chromosomes (PACs) have been isolated and used to localise the distal breakpoints of the two duplications. Linkage analysis of the familial case with a normal karyotype identified a recombination within the critical region. This recombination has been identified on the radiation hybrid map and defines the proximal end of the region of interest. We therefore propose that an imprinted gene for TNDM lies within an 18.72 cR3000 (approximately 5.4 Mb) interval on chromosome 6q24.1-q24.3 between markers D6S1699 and D6S1010.     

Homozygosity mapping of an autosomal recessive form of demyelinating Charcot-Marie-Tooth disease to chromosome 5q23-q33

Charcot-Marie-Tooth (CMT) disease is the most frequent inherited peripheral motor and sensory neuropathy characterised by chronic distal weakness with progressive muscular atrophy and sensory loss of the distal extremities. The dominant form of the disease is genetically heterogeneous but only one locus has been identified on chromosome 8q13- q21.1 for autosomal recessive CMT. By homozygosity mapping in a large Algerian kindred, we have assigned a second locus for autosomal recessive CMT to chromosome 5q23-33. Linkage analysis demonstrated that the same locus is involved in a second Algerian family with a demyelinating CMT. Haplotype reconstruction and determination of the minimal region of homozygosity restricts the candidate region to a 4 cM interval.      

Three region-specific microdissection libraries for the long arm of human chromosome 2, regions q33-q35, q31-q32, and q23-q24

Three region-specific libraries have been constructed from the long arm of human chromosome 2, including regions 2q33-35 (2Q2 library), 2q31-32 (2Q3) and 2q23-24 (2Q4). Chromosome microdissection and the Mbol linker-adaptor microcloning techniques were used in constructing these libraries. The libraries comprised hundreds of thousands of microclones in each library. Approximately half of the microclones in the library contained unique or low-copy number sequence inserts. The insert sizes ranged between 50 and 800 bp, with a mean of 130–190 bp. Southern blot analysis of individual unique sequence microclones showed that 70–94% of the microclones were derived from the dissected region. 31 unique sequence microclones from the 2Q2 library, 31 from 2Q3, and 30 from 2Q4, were analyzed for insert sizes, the hybridizing genomic HindIII fragment sizes, and cross-hybridization to rodent species. These libraries and the short insert microclones derived from the libraries should be useful for high resolution physical mapping, sequence-ready reagents for large scale genomic sequencing, and positional cloning of disease-related genes assigned to these regions, e.g. the recessive familial amyotrophic lateral sclerosis assigned to 2q33-q35, and a type I diabetes susceptibility gene to 2q31-q33.     

A novel locus for syndromic chronic idiopathic intestinal pseudo-obstruction maps to chromosome 8q23-q24

Chronic idiopathic intestinal pseudo-obstruction (CIIP) is a rare and severe clinical syndrome characterized by symptoms and signs of intestinal occlusion, in the absence of any mechanical obstruction of the gut lumen. In the attempt to identify the genetic basis of CIIP, we analyzed a Turkish pedigree with a high degree of consanguinity in which three siblings presented with a syndromic form of CIIP. All affected family members were characterized by recurrent, self-limiting subocclusive episodes, long-segment Barrett esophagus, and a variety of minor cardiac valve or septal defects. In some patients full-thickness intestinal biopsy samples were obtained and tissues were processed for immunohistochemistry using antibodies to different markers of the intestinal neuromuscular tract. Full-thickness biopsies of the gut wall showed abnormalities of both the neural and muscular components suggesting an underlying intestinal neuro-myopathy. Blood samples were collected for DNA extraction from each available family member and DNAs were genotyped using 382 microsatellites spanning the entire genome with the aim to take advantage of the homozygosity mapping approach. Linkage analysis identified a new syndromic locus on chromosome 8q23-q24 (multipoint LOD score=5.01). Our data strongly support the presence of a new genetic locus associated with CIIP, long-segment Barrett esophagus, and cardiac involvement on chromosome 8.