Genetic markers for idiopathic scoliosis on chromosome 19p 13.3 among Saudi Arabian girls: A pilot study

BACKGROUND AND OBJECTIVE:

Genetic locus linked to chromosome 19p for Adolescent idiopathic scoliosis (AIS) has been described. This study was carried out with the aim to find any significant linkage or association between three microsatellite markers (D19S216, D19S894, and DS1034) of chromosome 19p13.3 in Saudi Arabian girls with AIS.

MATERIALS AND METHODS:

In eleven unrelated Saudi Arabian girls who were treated for AIS with Cobb angle of ≥30 degrees and in 10 unrelated healthy individuals, linkage analysis was performed using parametric and nonparametric methods by use of GENEHUNTER version 2.1. Multipoint linkage analysis was used in specifying an autosomal dominant trait with a gene frequency of 0.01 and an estimated penetrance of 80% at the genotype and the allele level. Fisher''s exact test was used in the analysis of contingency tables for the D19S216, D19S894, and DS1034 markers.

RESULTS:

The analysis between the patient group and healthy girls showed that at genotypic level there was no significant association of the markers and scoliosis D19S216 (P = 0.21), D19S894 (P = 0.37), and DS1034 (P = 0.25). Whereas, at the allele level, there was statistically significant association between the marker DS1034 (P = 0.008) and no significant association with the other two markers D19S216 (P = 0.25) and D19S894 (P = 0.17).

CONCLUSIONS:

Our study shows that at genotypic level none of the markers reported earlier were associated with scoliosis but at allele level, marker DS1034 was significantly associated with patients with AIS. This allele marker on chromosome 19p appears important in the etiology of AIS.     

Homozygosity mapping of a Weill-Marchesani syndrome locus to chromosome 19p13.3-p13.2

Weill-Marchesani syndrome (WMS) is a rare disease characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities, including microspherophakia, ectopia lentis, and glaucoma. Both autosomal recessive and autosomal dominant modes of inheritance have been described in association with WMS. We have performed a genome-wide search in two large consanguineous families of Lebanese and Saudian origin consistent with an autosomal recessive mode of inheritance. Here, we report the linkage of the disease gene to chromosome 19p13.3-p13.2 (Zmax=5.99 at theta=0 at locus D19S906). A recombination event between loci D19S905 and D19S901 defines the distal boundary, and a second recombination event between loci D19S221 and D19S840 defines the proximal boundary of the genetic interval encompassing the WMS gene (12.4 cM). We hope that our ongoing studies will lead to the identification of the disease-causing gene.     

Assignment of a locus for autosomal dominant idiopathic scoliosis (IS) to human chromosome 17p11

Idiopathic scoliosis (IS) is a spine deformity of unknown etiology. Family studies have suggested that IS may be inherited as a mendelian autosomal dominant trait. We have performed linkage analysis on a three-generation IS Italian family. A positive LOD score value of 3.20 at theta=0.00 was detected with marker D17S799 after a genome-wide scanning. Analysis of six flanking microsatellites confirmed the linkage and haplotype inspection defined an interval of about 20 cM between D17S947 and D17S798. This is the first locus reported for IS. We scored genes mapping in this interval and studied the heparan sulfotransferase genes as candidates on the basis of their biochemical role. No causative mutation was detected in the affected patients.     

The autosomal recessive nonsyndromic deafness locus DFNB72 is located on chromosome 19p13.3

We ascertained three consanguineous Pakistani families (PKDF291, PKDF335 and PKDF793) segregating nonsyndromic recessive hearing loss. The hearing loss segregating in PKDF335 and PKDF793 is moderate to severe, whereas it is profound in PKDF291. The maximum two-point LOD scores are 3.01 (D19S1034), 3.85 (D19S894) and 3.71 (D19S894) for PKDF291, PKDF335 and PKDF793, respectively. Haplotype analyses of the three families define a 1.16 Mb region of overlap of the homozygous linkage intervals bounded by markers D19S216 (20.01 cM) and D19S1034 (20.75 cM). These results define a novel locus, DFNB72, on chromosome 19p13.3. There are at least 22 genes in the 1.16 Mb interval, including PTPRS, ZNRF4 and CAPS. We identified no pathogenic variants in the exons and flanking intronic sequences of these three genes in affected members of the DFNB72 families. DFNB72 is telomeric to DFNB68, the only other known deafness locus with statistically significant support for linkage to chromosome 19p.     

A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3

Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D19S902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker D19S867, at a recombination fraction of.00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28-42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B).     

Genetic mapping of the Camurati-Engelmann disease locus to chromosome 19q13.1-q13.3

Camurati-Engelmann disease (CED [MIM 131300]), or progressive diaphyseal dysplasia, is an autosomal dominant sclerosing bone dysplasia characterized by progressive bone formation along the periosteal and endosteal surfaces at the diaphyseal and metaphyseal regions of long bones and cranial hyperostosis, particularly at the skull base. The gene for CED, or its chromosomal localization, has not yet been identified. We performed a genomewide linkage analysis of two unrelated Japanese families with CED, in which a total of 27 members were available for this study; 16 of them were affected with the disease. Two-point linkage analysis revealed a maximum LOD score of 7.41 (recombination fraction.00; penetrance 1.00) for the D19S918 microsatellite marker locus. Haplotype analysis revealed that all the affected individuals shared a common haplotype observed, in each family, between D19S881 and D19S606, at chromosome 19q13.1-q13.3. These findings, together with a genetic distance among the marker loci, indicate that the CED locus can be assigned to a 15.1-cM segment between D19S881 and D19S606.     

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.     

The locus for apolipoprotein CII is closely linked to the apolipoprotein E locus on chromosome 19 in man

Summary We have demonstrated close linkage between the genes for apolipoprotein E (apoE) and apolipoprotein CII (apoCII). Families segregating for apoE protein variants were screened for a DNA restriction fragment length polymorphism close to the apoCII gene by using an apoCII cDNA clone. The maximum lod score is 4.52 (sexes combined) at a recombination frequency of zero. Given linkage, it may be assumed that no recombinations have happened in altogether 33 observed meioses. It is therefore evident that the apoCII gene is situated on chromosome 19, close to the apoE gene.     

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.     

Evidence for a novel late-onset Alzheimer disease locus on chromosome 19p13.2

Late-onset familial Alzheimer disease (LOFAD) is a genetically heterogeneous and complex disease for which only one locus, APOE, has been definitively identified. Difficulties in identifying additional loci are likely to stem from inadequate linkage analysis methods. Nonparametric methods suffer from low power because of limited use of the data, and traditional parametric methods suffer from limitations in the complexity of the genetic model that can be feasibly used in analysis. Alternative methods that have recently been developed include Bayesian Markov chain-Monte Carlo methods. These methods allow multipoint linkage analysis under oligogenic trait models in pedigrees of arbitrary size; at the same time, they allow for inclusion of covariates in the analysis. We applied this approach to an analysis of LOFAD on five chromosomes with previous reports of linkage. We identified strong evidence of a second LOFAD gene on chromosome 19p13.2, which is distinct from APOE on 19q. We also obtained weak evidence of linkage to chromosome 10 at the same location as a previous report of linkage but found no evidence for linkage of LOFAD age-at-onset loci to chromosomes 9, 12, or 21.     

Mapping of the KHSRP gene to a region of conserved synteny on human chromosome 19p13.3 and mouse chromosome 17

The K homology-type splicing regulatory protein, KSRP, activates splicing through intronic splicing enhancer sequences. It is highly expressed in neural cells and is required for the neural-specific splicing of the c-src N1 exon. In this study, we mapped the gene (gene symbols KHSRP and Khsrp) to human chromosome 19 by using radiation hybrid panels and to mouse chromosome 17 by studying an interspecific backcross panel. Human KHSRP is a positional candidate gene for familial febrile convulsion and Cayman type cerebellar ataxia. Comparative analysis of the human and mouse genomes indicates that the KHSRP gene is located in regions of conserved synteny between the two species.     

A novel locus for split-hand/foot malformation associated with tibial hemimelia (SHFLD syndrome) maps to chromosome region 17p13.1-17p13.3

Split-hand/foot malformation (SHFM) associated with aplasia of long bones, SHFLD syndrome or Tibial hemimelia-ectrodactyly syndrome is a rare condition with autosomal dominant inheritance, reduced penetrance and an incidence estimated to be about 1 in 1,000,000 liveborns. To date, three chromosomal regions have been reported as strong candidates for harboring SHFLD syndrome genes: 1q42.2–q43, 6q14.1 and 2q14.2. We characterized the phenotype of nine affected individuals from a large family with the aim of mapping the causative gene. Among the nine affected patients, four had only SHFM of the hands and no tibial defects, three had both defects and two had only unilateral tibial hemimelia. In keeping with previous publications of this and other families, there was clear evidence of both variable expression and incomplete penetrance, the latter bearing hallmarks of anticipation. Segregation analysis and multipoint Lod scores calculations (maximum Lod score of 5.03 using the LINKMAP software) using all potentially informative family members, both affected and unaffected, identified the chromosomal region 17p13.1–17p13.3 as the best and only candidate for harboring a novel mutated gene responsible for the syndrome in this family. The candidate gene CRK located within this region was sequenced but no pathogenic mutation was detected.     

Genomic characterization of LIGHT reveals linkage to an immune response locus on chromosome 19p13.3 and distinct isoforms generated by alternate splicing or proteolysis.

LIGHT is a member of the TNF cytokine superfamily that signals through the lymphotoxin (LT)beta receptor and the herpesvirus entry mediator. LIGHT may function as a costimulatory factor for the activation of lymphoid cells and as a deterrent to infection by herpesvirus, which may provide significant selective pressure shaping the evolution of LIGHT. Here, we define the molecular genetics of the human LIGHT locus, revealing its close linkage to the TNF superfamily members CD27 ligand and 4-1BB ligand, and the third complement protein (C3), which positions LIGHT within the MHC paralog on chromosome 19p13.3. An alternately spliced isoform of LIGHT mRNA that encodes a transmembrane-deleted form is detected in activated T cells and gives rise to a nonglycosylated protein that resides in the cytosol. Furthermore, membrane LIGHT is shed from the cell surface of human 293 T cells. These studies reveal new mechanisms involved in regulating the physical forms and cellular compartmentalization of LIGHT that may contribute to the regulation and biological function of this cytokine.     

The human cardiac troponin I locus: assignment to chromosome 19p13.2–19q13.2

Summary The three major troponin I isoforms are encoded by separate genes and are expressed in a muscle-type-specific manner. A human cardiac troponin I cDNA has recently been isolated and used to establish the genomic location of the cardiac troponin I gene locus (designated TNNC1). By somatic cell hybrid analysis, the locus for TNNC1 maps to human chromosome 19 and can be localised to the region p13.2–q13.2     

Empirically derived maximal acceptable wait time for surgery to treat adolescent idiopathic scoliosis

Background

Prioritizing patients using empirically derived access targets can help to ensure high-quality care. Adolescent scoliosis can worsen while patients wait for treatment, increasing the risk of adverse events. Our objective was to determine an empirically derived access target for scoliosis surgery and to compare this with consensus-based targets

Methods

Two-hundred sixteen sequential patients receiving surgery for adolescent idiopathic scoliosis were included in the study. The main outcome was need for additional surgery. Logistic regression modeling was used to evaluate the relation between surgical wait times and adverse events and χ² analysis was used as the primary analysis for the main outcome.

Results

Of the 88 patients who waited longer than six months for surgery, 13 (14.8%) needed additional surgery due to progression of curvature versus 1.6% (2 of 128 patients) who waited less than six months for surgery (χ² analysis, p = 0.0001). Patients who waited longer than six months for surgery had greater progression of curvature, longer surgeries and longer stays in hospital. These patients also had less surgical correction than patients who waited less than six months for surgery (Wilcoxon–Mann–Whitney test, p = 0.011). All patients requiring additional surgeries waited longer than three months for their initial surgery. A receiver–operator characteristic curve also suggested a three-month wait as an access target. The adjusted odds ratio for an adverse event for each additional 90 days of waiting from time of consent was 1.81 (95% confidence interval 1.34–2.44). The adjusted odds ratio increased with skeletal immaturity and with the size of the spinal curvature at the time of consent.

Interpretation

A prolonged wait for surgery increased the risk of additional surgical procedures and other adverse events. An empirically derived access target of three months for surgery to treat adolescent idiopathic scoliosis could potentially eliminate the need for additional surgery by reducing progression of curvature. This is a shorter access target than the six months determined by expert consensus.Adolescent idiopathic scoliosis effects just over 2% of females aged 12–14 years.^1–3 Although only 10% of patients require surgery, spinal instrumentation and fusion for adolescent idiopathic scoliosis is the most common procedure done in pediatric orthopaedics.⁴ Patients who wait too long for scoliosis surgery may require additional surgery such as anterior release to achieve satisfactory correction of the spinal curvature. These patients may also need longer surgeries and may be at increased risk of complications such as increased blood loss, neurologic deficits or inadequate correction of the curvature.^5–14 Furthermore, as seen in other studies of wait times, patients and families can feel anxiety and prolonged suffering while waiting for treatment, which can negatively impact the quality of care.^15–19 Programs such as the Canadian Pediatric Surgical Wait Times Project have determined a maximal acceptable wait time for adolescent scoliosis through expert consensus (similar to how other surgical wait time targets have been determined).²⁰ Surprisingly, there has been little or no attention given to developing evidence-based access targets or maximal acceptable wait times for most treatments.²¹ The purpose of this study was to determine the maximal acceptable wait time for surgical correction of adolescent idiopathic scoliosis using an empirically based approach to minimize the possibility of adverse events related to progression of curvature.