CHD7 Gene Polymorphisms Are Associated with Susceptibility to Idiopathic Scoliosis

Department of Pediatrics, University of Iowa, Iowa City, Iowa, United States
The American Journal of Human Genetics (Impact Factor: 10.93). 05/2007; 80(5):957-65. DOI: 10.1086/513571
Source: PubMed


Idiopathic scoliosis (IS) is the most common spinal deformity in children, and its etiology is unknown. To refine the search for genes underlying IS susceptibility, we ascertained a new cohort of 52 families and conducted a follow-up study of genomewide scans that produced evidence of linkage and association with 8q12 loci (multipoint LOD 2.77; P=.0028). Further fine mapping in the region revealed significant evidence of disease-associated haplotypes (P<1.0 x 10-4) centering over exons 2-4 of the CHD7 gene associated with the CHARGE (coloboma of the eye, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness) syndrome of multiple developmental anomalies. Resequencing CHD7 exons and conserved intronic sequence blocks excluded coding changes but revealed at least one potentially functional polymorphism that is overtransmitted (P=.005) to affected offspring and predicts disruption of a caudal-type (cdx) transcription-factor binding site. Our results identify the first gene associated with IS susceptibility and suggest etiological overlap between the rare, early-onset CHARGE syndrome and common, later-onset IS.

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Available from: Anne Bowcock, Feb 03, 2014
    • "Concordance rates among monozygotic and bi-zygotic twins have been reported to range from 73% to 92% and 36% to 63%, respectively.1718 Gao et al.19 suggest evidence of linkage and association with the 8q12 loci. Through further investigations they discovered the first gene (CHD7) associated with susceptibility to AIS.19 Gurnett et al.20 published a report of a single multi-generational family in which AIS and pectus excavatum segregated as an autosomal dominant condition. "
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    ABSTRACT: A new era in the surgical treatment of adolescent idiopathic scoliosis (AIS) opened with the introduction of pedicle screw instrumentation, which provides 3-column vertebral fixation and allows major deformity correction on the coronal, sagittal, and axial planes. A steep learning curve can be expected for spinal surgeons to become familiar with pedicle screw placement and correction techniques. Potential complications including injury to adjacent neural, vascular, and visceral structures can occur due to screw misplacement or pull-out during correction maneuvers. These major complications are better recognized as pedicle screw techniques become more popular and may result in serious morbidity and mortality. Extensive laboratory and clinical training is mandatory before pedicle screw techniques in scoliosis surgery are put to practice. Wider application, especially in developing countries, is limited by the high cost of implants. Refined correction techniques are currently developed and these utilize a lesser number of pedicle anchors which are strategically positioned to allow optimum deformity correction while reducing the neurological risk, surgical time, and blood loss, as well as instrumentation cost. Such techniques can be particularly attractive at a time when cost has major implications on provision of health care as they can make scoliosis treatment available to a wider population of patients. Pedicle screw techniques are currently considered the gold standard for scoliosis correction due to their documented superior biomechanical properties and ability to produce improved clinical outcomes as reflected by health-related quality-of-life questionnaires. Ongoing research promises further advances with the future of AIS treatment incorporating genetic counseling and possibly fusionless techniques.
    No preview · Article · Mar 2013 · Indian Journal of Orthopaedics
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    • "Idiopathic scoliosis (IS) is the most common cause of spinal deformity in children, but the etiology of the disease has remained elusive. Recent research has found a strong association between mutations of the CHD7 gene and the development of IS [27]. The potential exists to replicate CHD7-mutation dependent IS in transgenic mice and to investigate intervention therapies in an accurate murine model. "
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    ABSTRACT: Spinal fusion is a common orthopaedic procedure that has been previously modeled using canine, lapine, and rodent subjects. Despite the increasing availability of genetically modified mouse strains, murine models have only been infrequently described. To present an efficient and minimally traumatic procedure for achieving spinal fusion in a mouse model and determine the optimal rhBMP-2 dose to achieve sufficient fusion mass. MicroCT reconstructions of the unfused mouse spine and human spine were compared to design a surgical approach. In phase 1, posterolateral lumbar spine fusion in the mouse was evaluated using 18 animals allocated to three experimental groups. Group 1 received decortication only (n = 3), Group 2 received 10 μg rhBMP-2 in a collagen sponge bilaterally (n = 6), and Group 3 received 10 μg rhBMP-2 + decortication (n = 9). The surgical technique was assessed for intra-operative safety, efficacy, access and reproducibility. Spines were harvested for analysis at 3 weeks (Groups 1, 2) and 1, 2, and 3 weeks (Group 3). In phase 2, a dose response study was carried out in an additional 18 animals with C57BL6 mice receiving sponges containing 0, 0.5, 1, 2.5, 5 μg of rhBMP-2 per sponge bilaterally. The operative procedure via midline access was rapid and reproducible, and fusion of the murine articular processes was found to be analogous to the human procedure. Unlike reports from other species, decortication alone (Group 1) yielded no new bone formation. Addition of rhBMP-2 (Groups 2 and 3) yielded a significant bone mass that bridged the L4-L6 vertebrae. The subsequent dose response experiment revealed that 0.5 μg rhBMP-2 per sponge was sufficient to create a fusion mass. We describe a new approach for mouse lumbar spine fusion that is safe, efficient, and highly reproducible. The technique we employed is analogous to the human midline procedure and may be highly suitable for genetically modified mouse models.
    Full-text · Article · Jan 2013 · Journal of Orthopaedic Surgery and Research
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    • ". In 53 families with isolated scoliosis, a genome-wide scan showed linkage and association with 8q12 loci [Gao et al., 2007]. "
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    ABSTRACT: CHD7 is a member of the chromodomain helicase DNA-binding (CHD) protein family that plays a role in transcription regulation by chromatin remodeling. Loss-of-function mutations in CHD7 are known to cause CHARGE syndrome, an autosomal-dominant malformation syndrome in which several organ systems, for example, the central nervous system, eye, ear, nose, and mediastinal organs, are variably involved. In this article, we review all the currently described CHD7 variants, including 183 new pathogenic mutations found by our laboratories. In total, we compiled 528 different pathogenic CHD7 alterations from 508 previously published patients with CHARGE syndrome and 294 unpublished patients analyzed by our laboratories. The mutations are equally distributed along the coding region of CHD7 and most are nonsense or frameshift mutations. Most mutations are unique, but we identified 94 recurrent mutations, predominantly arginine to stop codon mutations. We built a locus-specific database listing all the variants that is easily accessible at In addition, we summarize the latest data on CHD7 expression studies, animal models, and functional studies, and we discuss the latest clinical insights into CHARGE syndrome.
    Full-text · Article · Aug 2012 · Human Mutation
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