Localization of a novel locus for hereditary nail dysplasia to chromosome 17q25.1-17q25.3

We report on a six-generation Pakistani consanguineous family with autosomal recessive transmission of a form of hereditary nail dysplasia. Affected individuals presented with onycholysis of fingernails and anonychia of toenails. Associated abnormalities of ectodermal appendages were not observed in any of the affected individuals. Linkage has been established to chromosome 17q. A maximum multipoint analysis logarithm of the odds ratio score of 4.85 was obtained at marker D17S1301. Due to the consanguineous nature of this kindred, the gene for nail dysplasia is probably contained within a 5.0-cM (3 MB on the sequence-based physical map) region of homozygosity flanked by markers D17S1807 and D17S937.     

Mutation analysis of a putative sialyltransferase gene, the SFRS2 splicing factor gene and the c-myb ET-locus in two families with hereditary neuralgic amyotrophy (HNA)

HNA is an autosomal dominant recurrent focal neuropathy involving the brachial plexus. The etiology of HNA is unknown but the genetic defect most likely affects a non-neuronal tissue. We previously described linkage to chromosome 17q24–q25 in two HNA-families. Here we report the mutation analysis of two candidate genes: a cDNA encoding a putative sialyltransferase and the SFRS2 splicing factor including the c-myb ET-locus which is encoded on the opposite strand of the SFRS2 gene. The complete protein coding regions of both genes were studied by direct DNA sequencing. We did not find a disease associated mutation indicating that these genes are most likely not involved in the pathogenesis of HNA. However, we identified and characterized a rare Ava II polymorphism in the SFRS2 gene and detected a sequencing error, leading to an amino acid change (Val11Leu) in the published sequence of the putative sialyltransferase.     

Genetic refinement of dominant optic atrophy (OPA1) locus to within a 2 cM interval of chromosome 3q.

Autosomal dominant optic atrophy (OPA, MIM 165500) is an eye disease characterised by variable optic atrophy and reduction in visual acuity. It has an insidious onset in the first decade of life and is clinically highly heterogeneous. It is associated with a centrocecal scotoma of varying size and density and an acquired blue-yellow dyschromatopsia. Recent studies of three large Danish pedigrees have mapped a gene for dominant optic atrophy (OPA1) to a 10 cM region on chromosome 3q, between markers D3S1314 and D3S1265 (3q28-qter). Genetic linkage analysis in five British pedigrees confirms mapping to chromosome 3q28-qter. Haplotype analysis of a seven generation pedigree positions the disease causing gene between loci D3S3590 and D3S1305, corresponding to a genetic distance of 2 cM. This represents a significant linkage refinement and should facilitate positional cloning of the disease gene.     

Segmental duplications flank the multiple sclerosis locus on chromosome 17q

Large chromosomal rearrangements, duplications, and inversions are relatively common in mammalian genomes. Here we report interesting features of DNA strands flanking a Multiple Sclerosis (MS) susceptibility locus on Chromosome 17q24. During the positional cloning process of this 3-Mb locus, several markers showed a radiation hybrid clone retention rate above the average (1.8-fold), suggestive for the existence of duplicated sequences in this region. FISH studies demonstrated multiple signals with three of the tested regional BACs, and 24 BACs out of 187 showed evidence for duplication in shotgun sequence comparisons of the 17q22-q24 region. Specifically, the MS haplotype region proved to be flanked by palindromic sequence stretches and by long segmental intrachromosomal duplications in which highly homologous DNA sequences (>96% identity) are present at both ends of the haplotype. Moreover, the 3-Mb DNA segment, flanked by the duplications, is inverted in the mouse genome when compared with the orientation in human and chimp. The segmental duplication architecture surrounding the MS locus raises the possibility that a nonallelic homologous recombination between duplications could affect the biological activity of the regional genes, perhaps even contributing to the genetic background of MS.     

Genetic refinement of the chromosome 5q lattice corneal dystrophy type I locus to within a 2 cM interval.

Lattice corneal dystrophy type I (LCDI) is a relatively common corneal dystrophy which can cause severe visual impairment. Recent studies have suggested a genetic localisation for the disease to chromosome 5q. Independent genetic linkage analysis in a six generation LCDI pedigree confirmed linkage to the 5q region bounded by marker loci IL9 and D5S436 suggesting genetic homogeneity. A maximum two point lod score of 7.51 (theta = 0.03) was obtained with marker D5S393. Multipoint and haplotype data positioned the disease between loci D5S393 and D5S396 corresponding to a genetic distance of 2cM, thus refining linkage sufficiently to allow for physical mapping of this disorder.     

A locus for hereditary hypotrichosis localized to human chromosome 18q21.1

Hereditary hypotrichosis is a rare autosomal recessive condition characterized clinically by alopecia. Three consanguineous kindreds with multiple affected individuals were ascertained from different regions of Pakistan. A novel hypotrichosis locus was mapped to a 5.5 cM region on chromosome 18q21.1. A maximum two-point LOD score of 5.25 was obtained at marker D18S36 (theta=0.0). Three genes each for desmoglein and desmocollin proteins are located in this region. The expression in epidermal desmosomes and their connection to the keratin intermediate filaments make these genes excellent candidates for recessive hypotrichosis.     

A third locus for hereditary haemorrhagic telangiectasia maps to chromosome 12q

Hereditary haemorrhagic telangiectasia (HHT) or Rendu-Osler-Weberdisease is an autosomal dominant vascular disorder which associatesepistaxis, mucocutaneous and visceral telangiectases, and recurrenthaemorrhage with chronic anaemia and visceral shuntings. Recently,the tumour growth factor (TGF)ß binding protein endoglinlocalized to 9q33–34 was identified as responsible forHHT in several large kindreds with pulmonary arteriovenous malformations(PAVMs). Additional linkage studies demonstrated that HHT isa genetically heterogeneous disorder with families unlinkedto this region of 9q. In the families in which HHT was not linkedto chromosome 9, less PAVMs were present. Furthermore, in oneof these families, HHT was found linked to 3p22, where the TGFßII receptor is located. In this linkage study, we have analysed DNA from two families,In which HHT was unlinked to chromosome 9q and 3p, and PAVMswere absent, with a series of genetic markers on the centromericregion of chromosome 12. Using two-point linkage analysis, asignificant lod score of 2^zmx = 7.86 at     

Genetic linkage of the tricho-dento-osseous syndrome to chromosome 17q21

Tricho-dento-osseous syndrome (TDO), MIM# 190320, is transmitted as a highly penetrant autosomal dominant trait that is characterized by variable clinical expression. The principal clinical features include kinky/curly hair in infancy, enamel hypoplasia, taurodontism, as well as increased thickness and density of cranial bones. Possible genetic linkage has been reported for TDO with the ABO blood group locus, but the gene defect remains unknown. We have identified four multiplex families (n = 63, 39 affected, 24 unaffected) from North Carolina segregating TDO. We previously have excluded a major locus for TDO in the ABO region for these families. Utilizing a genome-wide search strategy, we obtained conclusive evidence for linkage of the TDO syndrome locus to markers on chromosome 17q21 (D17S791, Z max = 10.54, Theta = 0.00) with no indication of genetic heterogeneity. Multipoint analysis suggests the TDO locus is located in a 7 cM chromosomal segment flanked by D17S932 and D17S941. This finding represents the first step towards isolation and cloning of the TDO gene. Identification of this gene has important implications for understanding normal and abnormal craniofacial development of hair, teeth and bone.      

Dysmorphic syndrome of hereditary neuralgic amyotrophy associated with a SEPT9 gene mutation--a family study

We report a family in which two siblings presented with an apparent dysmorphic syndrome, including hypotelorism, blepharophimosis, slight ptosis, epicanthal folds, microstomia and dysmorphic ears. One sibling had a cleft palate. Initially, blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) was suspected; however, mutation of the FOXL2 gene was not detected. Moreover, the patients' father and paternal grandmother had experienced recurrent episodes of unilateral brachial neuritis and were diagnosed to have hereditary neuralgic amyotrophy (HNA). HNA is a rare, inherited form of brachial neuritis whose phenotypic spectrum may include hypotelorism, cleft palate and other minor dysmorphisms. HNA maps to chromosome 17q25 and is associated with mutations in the SEPT9 gene. After confirming a heterozygous SEPT9 mutation (R88W) in the father and his mother, it became apparent that the dysmorphic features in the children were part of HNA and that previous complaints of the daughter, erroneously diagnosed as pronatio dolorosa and then epiphysiolysis of the capitellum humeri, were in fact a first neuralgic pain attack. Both children were shown to have inherited the paternal SEPT9 mutation. Wider recognition of HNA as a syndromic disorder may facilitate its diagnosis in affected young persons who may not yet have manifested episodes of brachial neuritis.     

Further refinement of the Usher 2A locus at 1q41.

Usher syndrome (USH) is characterised by congenital sensorineural hearing loss and progressive pigmentary retinopathy. All three subtypes (USH1, USH2, and USH3) are inherited as recessive traits. People with Usher type 2 (USH2) have normal vestibular responses and moderate to severe hearing loss. These syndromes have been found to be genetically heterogeneous, with a single locus for USH2 at 1q41 (USH2A), six loci for USH1, and one for USH3. Some USH2 families have been excluded from the 1q41 locus suggesting that a second, as yet unidentified, locus (USH2B) must exist. Linkage studies suggest that around 90% of USH2 families are USH2A. Four USH2 families were analysed for linkage to markers flanking the USH2A locus. In one of these families a recombination event was observed in an affected subject which excludes the USH2A gene from proximal to the marker AFM143XF10 and defines this as the new centromeric flanking marker for the USH2A locus. A further recombination event in another patient from this family confirmed AFM144XF2 as the telomeric flanking marker. The interval between these polymorphic markers is estimated to be 400 kb. This region is completely contained in each of three YACs from the CEPH library: 867g9, 919h3, and 848b9. This refinement more than halves the critical genetic interval and will greatly facilitate positional cloning of the USH2A gene.     

Homozygosity mapping of a Desbuquois dysplasia locus to chromosome 17q25.3

Desbuquois dysplasia is a rare autosomal recessive chondrodysplasia characterised by short stature, joint laxity, facial dysmorphism, a "Swedish key" appearance of the proximal femur, advanced carpal and tarsal bone age, and hand anomalies consisting of phalangeal dislocations and an extra ossification centre distal to the second metacarpal. However, the latter changes are not consistently observed in all Desbuquois patients, defining two distinct groups, based on the presence or absence of hand anomalies. We have performed a genome wide search in four inbred Desbuquois families with typical hand anomalies originating from France, Sri-Lanka, the United Arab Emirates, and Morocco. Here, we report on the mapping of a disease gene to chromosome 17q25.3 (Zmax=4.61 at theta=0 at locus D17S1806) in the 9.5 cM interval defined by loci D17S802 and D17S1822. The present study supports the genetic homogeneity of the clinical subtype with hand anomalies and will hopefully help in identifying the Desbuquois dysplasia gene.     

Cia27 is a novel non-MHC arthritis severity locus on rat chromosome 10 syntenic to the rheumatoid arthritis 17q22-q25 locus

Cia27 on rat chromosome 10 is a collagen-induced arthritis (CIA) severity quantitative trait locus originally identified in a study of (DA x ACI) F2. As an initial step towards the positional cloning of the Cia27 gene, a 17 cM (21 Mb) interval from the DA strain (arthritis-susceptible) containing the two-logarithm of odds support interval comprising Cia27 was introgressed into the ACI (arthritis-resistant) background through genotype-guided congenic breeding. ACI.DA(Cia27) congenics developed a significantly more severe form of arthritis (CIA), with a 5.9-fold increase in median arthritis severity index, a parameter known to correlate with synovial inflammation, and cartilage and bone erosions, compared with ACI (P< or =0.001). The arthritis severity enhancing effect could be detected from day 21 onwards. Rats heterozygous at the congenic interval developed a disease similar to ACI rats, suggesting that DA alleles operate in a recessive manner. Levels of autoantibodies anti-rat type II collagen did not correlate with arthritis severity. Synovial tissue mRNA levels of interleukin-1beta (IL-1beta) were significantly increased in ACI.DA(Cia27) congenics compared with ACI. These results demonstrate that Cia27 harbors a novel arthritis severity regulatory gene. The identification of this gene should facilitate the identification of the rheumatoid arthritis gene mapped to the human syntenic region on chromosome 17q22-q25.     

Genetic and physical mapping of the Treacher Collins syndrome locus: refinement of the localization to chromosome 5q32-33.2.

Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development, the locus for which has been chromosomally localized to 5q31-34. We have isolated four hypervariable microsatellite markers (heterozygosity values range from 0.70 to 0.89) which have been mapped to distal 5q. Fifteen unrelated TCOF1 families have been analyzed for linkage to these markers. There is strong evidence demonstrating linkage to all of these markers; the strongest support for positive linkage being provided by the marker IG52, with a maximum pairwise lod score of 9.77 at a recombination fraction of 0.055. Analysis of recombinant individuals, physical mapping by fluorescence in situ hybridization and genetic linkage analysis demonstrated that the TCOF1 locus was flanked proximally by the loci 2C7 and 2D10, and distally by the loci IG26 and IG52 with a maximum lod score of 14.4, as assessed by multipoint linkage analysis. The refinement of the localization of the TCOF1 locus to 5q32-33.2, with flanking markers, represents an important step towards the identification of the mutated gene itself.     

Recurrent brachial plexus neuropathy in a family with subtle dysmorphic features-a case of hereditary neuralgic amyotrophy

Brachial plexus neuropathy is a disorder which usually occurs sporadically, and is characterized by pain and varying degrees of weakness in one or both upper limbs. Some patients experience recurrent episodes. The hereditary form is usually associated with dysmorphic features. We describe a mother and son with recurrent episodes. Despite very slight dysmorphic features, we believe this is a case of the inherited form.     

Severe Silver-Russell syndrome and translocation (17;20) (q25;q13)

An 8-year-8-month-old girl with Silver-Russell syndrome (SRS) and a paternally inherited balanced t(17;20)(q25;q13) is described. This observation suggests that an SRS gene(s) maps on chromosome 17 or 20 and that the patient phenotype resulted from either unmasking of heterozygosity or genomic imprinting via paternal disomy.     

Distal hereditary motor neuropathy type II (distal HMN II): mapping of a locus to chromosome 12q24

The distal hereditary motor neuropathy (distal HMN) or the spinal form of Charcot-Marie-Tooth (CMT) disease is an exclusively motor disorder of the peripheral nervous system. The disorder clinically resembles the hereditary motor and sensory neuropathies (HMSN) type I and type II or CMT type 1 and type 2. Distal HMN might also be related to the spinal muscular atrophies (SMA) since, in both disorders, the lower motor neurons are affected. Electrophysiological and neuropathological examinations of peripheral nerves show the absence of sensory involvement. We performed a genome search in an extended Belgian family with autosomal dominant distal HMN type II. Significant linkage was obtained with markers located at chromosome 12q24, and the gene for distal HMN II was assigned to the 13 cM interval between D12S86 and D12S340.      

Polymorphisms and haplotypes of the chromosome locus 17q12-17q21.1 contribute to adult asthma susceptibility in Slovenian patients

One of the major asthma susceptibility loci is 17q12-17q21.1, but the relationship between this locus and adult asthma is unclear. Association analysis of 13 single nucleotide polymorphisms (SNPs) and haplotypes from 17q12-17q21.1 was performed in 418 adult patients with asthma and 288 controls from Slovenia. Single SNP analysis revealed only marginal associations with adult asthma for SNPs located in GSDMA, GSDMB, ORMDL3 and ZPBP2 genes, and rs7219080 was the most highly associated. Analyses of asthma phenotypes found no association with atopy or lung function, but rs2305480 and rs8066582 were associated with childhood asthma and rs9916279 was associated with asthma in smokers. Notably, haplotypes consisting of rs9916279, rs8066582, rs1042658, and rs2302777 harbouring PSMD3, CSF3 and MED24 genes were highly associated with asthma. The four most common haplotypes, TCCG, TTTA, CCCA and TTCA, were more frequent in patients with asthma, whereas TTCG, TCCA, TCTA and TTTG were more frequent in controls. Only 3% of asthma patients belonged to haplotypes TTCG, TCCA, TCTA and TTTG compared with nearly one-third (31%) of controls. Associations confirmed that the 17q12-17q21.1 locus harbours a genetic determinant for asthma risk in adults and suggest that in addition to the previously known ORMDL3-GSDM locus, CSF3-PSMD3-MED24 also plays a role in asthma pathogenesis.     

Novel case of del(17)(q23.1q23.3) further highlights a recognizable phenotype involving deletions of chromosome (17)(q21q24)

We report on a girl with a phenotype and developmental profile initially suggestive of Angelman syndrome. Subsequently she was shown to have an interstitial deletion of the long arm of chromosome 17; [del(17-q23.1q23.3)], the smallest unique cytogenetic deletion in this region documented to date. These findings and those of 4 others from the literature, with overlapping deletions of 17q and breakpoints between 17q21-17q24, are reviewed and compared. Similar phenotypic findings include growth retardation, global developmental delay, and specific musculoskeletal and craniofacial anomalies. The size of the specific deletion, and the proximal and distal breakpoints at this region of chromosome 17q, appear to be important in determining morbidity from cardiac involvement and may affect the extent of developmental delay. Am. J. Med. Genet. 71:275–279, 1997. © 1997 Wiley-Liss, Inc.