At the Zorab Symposium in Oxford, 2006, we showed that semicircular canal (SCC) anomalies occurring with posterior basicranium asymmetry affect the oculovestibular system in human beings. As a consequence, we proposed the hypothesis of a descending direct vestibulospinal and cognitive top-down effect on some scoliosis. We will show that some SCC anomalies detected with MRI modelling are malformations frequently found in scoliosis. 445 patients (323 women, mean age 21 years; 122 men, mean age 24 years) with instability, imbalance, and spatial disorientation were submitted to T2 MRI modelling. 95 of 445 patients had scoliosis: 57 thoracolumbar scoliosis, 24 thoracic scoliosis, and 14 lumbar deformation. We processed the data acquired with G.E.MRI (1.5T), T2- 3D Fiesta with a set of Brainvisa modules (http://brainvisa.info/).Introduction
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Clinical studies have shown distinct differences in later-onset idiopathic scoliosis (IS) between men and women, including curve severity, stiffness, and ease of operative intervention. Therefore, significant scoliosis in men was used as criteria to create a phenotypical subset of families with IS. The goal of this study is to identify genetic determinants that relate specifically to men with a scoliotic curvature of 30° or more. We identified 25 families (208 individuals) in which a male was diagnosed with 30° or more IS curvature in adolescence. 123 individuals were affected (48 male; 75 female), and 85 were unaffected (45 male; 40 female). Initially, a genomic screen was done with a modified CHLC (version 9) marker set. After initial linkage analyses, the group underwent finemapping with a custom single-nucleotide polymorphism (SNP) panel and ABI Taqman methodology on an ABI 377 platform. The initial genome-wide screen and subsequent analyses were analysed by model-independent linkage analysis with SIBPAL (SAGE, version 5).Introduction
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Kyphoscoliosis is defined by a structural lateral curvature of the spine of 10° or more and an excessive thoracic kyphotic curve of 40° or more. Genetic analyses of families in which two or more members had kyphoscoliosis identified a 3·5 Mb area on chromosome 5p containing three genes of the Iroquois (IRX) homeobox family, Exons and highly conserved non-coding regions (HNCRs) 500 kb upstream and downstream fromIntroduction
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Idiopathic scoliosis (IS) has been associated with several genetic loci in varying study populations, reflecting the disorder's genetic complexity. One region of interest is on chromosome 17, flanking regions linked to neurofibromatosis type 1 (NF1). This region is of particular relevance because the most common osseous manifestation in NF1 is scoliosis (10–30% of patients). This alludes to a potential genetic correlation within this region affecting spinal development or stability. The objective of this research is to identify candidate genes within this region that are statistically linked to IS. An initial population of IS families recruited through approval by the institutional review board (202 families; 1198 individuals) had DNA harvested from blood, and underwent genomic screening, finemapping, and statistical analyses. We identified a specific familial subset: families with males having undergone surgery for scoliosis (17 families, 147 individuals). The initial genome-wide scan indicated that this subset was linked to chromosome 17q.11.2. The most prominent marker, D17s975, (p=0·0003) at 25.12 Mb is adjacent to the NF1 deletional region. We then analysed a custom panel of single-nucleotide polymorphisms (SNPs) extending from 18·30–31·47 Mb for linkage through Taqman SNP assay protocol. With allele specific fluorescent tags, allelic discrimination was done with real-time PCR.Introduction
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Studies of the vestibular system in patients with idiopathic scoliosis (IS) have shown abnormalities in the semicircular canals (SCC) and the basicranium. Rousie (2008) revealed a statistically increased incidence of structural anomalies in the SCCs with three-dimensional computer generated modelling. Some of these findings were replicated in a small population by Cheng (2010). The primary goals of this investigation are verification of SCC abnormalities of patients with IS versus controls with use of three-dimensional modelling with subsequent development of a unique phenotypical classification. Our long-term goal is to provide new direction for hypothesis directed identification and characterisation of genes causally related to IS. 20 patients with IS and 20 controls matched for age and sex will be identified through the clinic with approval from the institutional review board. Power analyses were done to detect the difference in distributions as the proportion of fisher tests with p values less than 0·05. A sample size of 20 per group gives 86–99% power to realise results under conservative assumptions. IS patients and controls undergo vestibular system examination via T2 MRI imaging. Extracted data are evaluated by a team including Dr Rousie, ENT, radiology, and orthopaedic surgery. DNA is extracted with Gentra Puregene kits from Qiagen (Valencia, CA, USA). Developmental genes related to SCC and axial somatogenesis are being identified through a bioinformatics approach, targeting known IS genomic loci. Custom single-nucleotide polymorphism panels, statistical linkage, and association will identify genes of significance for sequencing.Introduction
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