Etiology Of Adolescent Idiopathic Scoliosis Research Articles

Prediction of adolescent idiopathic scoliosis with machine learning algorithms using brain volumetric measurements.

It is known that neuroanatomical and neurofunctional changes observed in the brain, brainstem and cerebellum play a role in the etiology of adolescent idiopathic scoliosis (AIS). This study aimed to investigate whether volumetric measurements of brain regions can be used as predictive indicators for AIS through machine learning techniques. Patients with a severe degree of curvature in AIS (n = 32) and healthy individuals (n = 31) were enrolled in the study. Volumetric data from 169 brain regions, acquired from magnetic resonance imaging (MRI) of these individuals, were utilized as predictive factors. A comprehensive analysis was conducted using the twelve most prevalent machine learning algorithms, encompassing thorough parameter adjustments and cross-validation processes. Furthermore, the findings related to variable significance are presented. Among all the algorithms evaluated, the random forest algorithm produced the most favorable results in terms of various classification metrics, including accuracy (0.9083), AUC (0.993), f1-score (0.970), and Brier score (0.1256). Additionally, the most critical variables were identified as the volumetric measurements of the right corticospinal tract, right corpus callosum body, right corpus callosum splenium, right cerebellum, and right pons, respectively. The outcomes of this study indicate that volumetric measurements of specific brain regions can serve as reliable indicators of AIS. In conclusion, the developed model and the significant variables discovered hold promise for predicting scoliosis development, particularly in high-risk individuals.

Neurophysiological, balance and motion evidence in adolescent idiopathic scoliosis: A systematic review.

Adolescent idiopathic scoliosis (AIS) is a spinal deformity that affects approximately 4% of the world's population. Several hypotheses regarding the etiology of AIS have been investigated. In the last decades, impaired visual-spatial perception, alterations in spatial body orientation and sensory integration deficits have been documented. We aimed to summarize the neurophysiological, balance, and motion evidence related to AIS published in the last fifteen years, between January 2008 and April 2023. Both observational and interventional studies were considered. Only studies using quantitative assessment methods, such as electroencephalography (EEG), electromyography (EMG), magnetic resonance imaging (MRI), somatosensory evoked potentials, force platform, or motion capture, were included. 1250 eligible records identified from online database searching were filtered by duplicate removal, title and abstract screening, and qualitative analysis. 61 articles met the inclusion criteria (i.e., Cobb range 10°-35°, age range 10-18 years) and were summarized. We found significant evidence of impaired standing balance in individuals with AIS who greatly rely on visual and proprioceptive information to stay upright. EMG studies frequently reported an increased activity on the convex side of the intrinsic spinae muscles. EEG data show increased delta and theta power, higher alpha peak frequencies, and significant suppression in the alpha and beta bands in subjects with AIS during standing tasks. MRI studies report changes in white matter structures, differences in the vestibular system, and abnormal cortical activations over motor-related areas in subjects with AIS. Bracing appears to be an effective treatment for AIS, leading to improvements in static balance and gait. Methodological issues prevent reliable conclusions about the effects of other treatment options. This review underscores the importance of quantitative assessment methods to explore the etiology and pathophysiology of AIS. Further research is needed to measure the impact of physical therapy and orthotic treatments on the neurophysiological mechanisms of the disease.

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Adolescent Idiopathic Scoliosis (AIS) is a three-dimensional spine deformity with lateral curvature having a Cobb angle exceeding 10° in the individual. It affects about 1-4 percent of adolescents globally and more frequently occurs in females than males. Despite the extensive research carried out on AIS, its aetiology is not known yet. However, several genetic studies suggest the contribution of various genetic variants in the possible aetiology of AIS. This review summarises the genetic association studies, including linkage, candidate as well as genome-wide association studies that were carried out globally on AIS and also categorised the associated genes in different biological pathways such as neurodevelopmental, hormone-related, cartilage and bone development pathways, based on their potential functional roles in the respective pathway, to understand the pathology of the disorder.

Experimental protocol to investigate cortical, muscular and body representation alterations in adolescents with idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is the most common form of scoliosis. AIS is a three-dimensional morphological spinal deformity that affects approximately 1-3% of adolescents. Not all factors related to the etiology of AIS have yet been identified. The primary aim of this experimental protocol is to quantitatively investigate alterations in body representation in AIS, and to quantitatively and objectively track the changes in body sensorimotor representation due to treatment. Adolescent girls with a confirmed diagnosis of mild (Cobb angle: 10°-20°) or moderate (21°-35°) scoliosis as well as age and sex-matched controls will be recruited. Participants will be asked to perform a 6-min upright standing and two tasks-named target reaching and forearm bisection task. Eventually, subjects will fill in a self-report questionnaire and a computer-based test to assess body image. This evaluation will be repeated after 6 and 12 months of treatment (i.e., partial or full-time brace and physiotherapy corrective postural exercises). We expect that theta brain rhythm in the central brain areas, alpha brain rhythm lateralization and body representation will change over time depending on treatment and scoliosis progression as a compensatory strategy to overcome a sensorimotor dysfunction. We also expect asymmetric activation of the trunk muscle during reaching tasks and decreased postural stability in AIS. Quantitatively assess the body representation at different time points during AIS treatment may provide new insights on the pathophysiology and etiology of scoliosis.

Association of polymorphism in leptin receptor gene with susceptibility of adolescent idiopathic scoliosis.

Abnormal leptin bioavailability has play key roles in the etiology of adolescent idiopathic scoliosis (AIS). Both leptin and its receptor levels may be modulated by the presence of genetic polymorphisms. This study aimed to evaluate the role of polymorphisms in the leptin (LEP) and its main receptor (LEPR) genes in the AIS susceptibility in girls. A retrospective case-control study was conducted with 189 AIS and 240 controls. LEP rs2167270 and LEPR rs2767485 polymorphisms were genotyped using a TaqMan validated assay. Associations were evaluated by odds ratios (OR) and 95% confidence intervals (CI). The AIS group showed a predominance of girls under 18years old (n = 140, 74.1%), 148 (78.3%) had low or normal BMI, 111 (58.7%) had Cobb ≥ 45º and 130 (68.7%) were skeletally mature. Minor allele frequencies of rs2167270 and rs2767485 were 35.7% and 18.3%, for AIS and 35.6% and 25.4% for controls, respectively. LEPR rs2767485 T and TC + TT were associated with higher risk of AIS (OR = 1.53; 95% CI = 1.09-2.13 and OR = 1.84; 95% CI = 1.69-2.01, respectively), since CC genotype was only present in the control group. In addition, the LEP rs2167270 GA + AA was more frequent in low weight group (BMI ≤ 24.9) of girls with AIS. There was no significant association between LEP rs2167270 and AIS susceptibility, and LEPR rs2767485 and BMI. The LEPR rs2767485 was associated with the genetic susceptibility of AIS and LEP rs2167270 with low BMI. These data can contribute to the identification of genetic biomarkers to improve the diagnosis and treatment.

A Genetic Variant of FAM46A is Associated With the Development of Adolescent Idiopathic Scoliosis in the Chinese Population.

A genetic case-control study. To replicate recently reported genetic loci associated with adolescent idiopathic scoliosis (AIS) in the Chinese Han population, and to determine the relationship between gene expression and the clinical features of the patients. A recent study conducted in the Japanese population identified several novel susceptible loci, which might provide new insights into the etiology of AIS. However, the association of these genes with AIS in other populations remains unclear. A total of 1210 AIS and 2500 healthy controls were recruited for the genotyping of 12 susceptibility loci. Paraspinal muscles used for gene expression analysis were obtained from 36 AIS and 36 patients with congenital scoliosis. The difference regarding genotype and allele frequency between patients and controls was analyzed by χ 2 analysis. The t test was performed to compare the target gene expression level between controls and AIS patients. Correlation analysis was performed between gene expression and phenotypic data, including Cobb angle, bone mineral density, lean mass, height, and body mass index. Four SNPs, including rs141903557, rs2467146, rs658839, and rs482012, were successfully validated. Allele C of rs141903557, allele A of rs2467146, allele G of rs658839, and allele T of single nucleotide polymorphism rs482012 showed significantly higher frequency in patients. Allele C of rs141903557, allele A of rs2467146, allele G of rs658839, and allele T of rs482012 could notably increase the risk of AIS patients, with an odds ratio of 1.49, 1.16, 1.11, and 1.25, respectively. Moreover, tissue expression of FAM46A was significantly lower in AIS patients as compared with controls. Moreover, FAM46A expression was remarkably correlated with bone mineral density of patients. Four SNPs were successfully validated as novel susceptibility loci associated with AIS in the Chinese population. Moreover, FAM46A expression was associated with the phenotype of AIS patients.

The relationship between minor coronal asymmetry of the spine and measures of spinal sagittal shape in adolescents without visible scoliosis

The purpose of this work is to identify what features of overall spinal sagittal shape are associated with coronal asymmetry in those without scoliosis. Using a longitudinal analysis of Integrated Shape Imaging System 2 (ISIS2) surface topography images of those without scoliosis, measures of coronal asymmetry, along with measures of spinal sagittal shape (kyphosis, lordosis and sagittal imbalance, which is a measure of the position of the top of the thoracic spine relative to the sacrum) were analysed using linear mixed effect models (LMEM), which is a method of analysing the components of a complex model (such as that describing overall spinal shape), to ascertain the relative relationships between the parameters. Data was also analysed when subdivided for the anatomical level of coronal asymmetry (thoracic or thoracolumbar/lumbar pattern). There were 784 measures from 196 children. Kyphosis had little effect on coronal asymmetry for males and females, lordosis increased with coronal asymmetry in females only and sagittal imbalance increased with coronal asymmetry in males only. The results of the LMEM modelling were that the parameters related to coronal asymmetry were lordosis and sagittal imbalance. In thoracic coronal asymmetry, whilst lordosis was predominant, kyphosis played more of a role. In thoracolumbar/lumbar coronal asymmetry, lordosis and sagittal imbalance were the larger coefficients. Coronal asymmetry of the spine in those without scoliosis is related to features of spinal sagittal shape, particularly lordosis and sagittal imbalance. This knowledge adds to the understanding of the aetiology of adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis : a review of aetiological theories of a multifactorial disease.

Adolescent idiopathic scoliosis (AIS), defined by an age at presentation of 11 to 18 years, has a prevalence of 0.47% and accounts for approximately 90% of all cases of idiopathic scoliosis. Despite decades of research, the exact aetiology of AIS remains unknown. It is becoming evident that it is the result of a complex interplay of genetic, internal, and environmental factors. It has been hypothesized that genetic variants act as the initial trigger that allow epigenetic factors to propagate AIS, which could also explain the wide phenotypic variation in the presentation of the disorder. A better understanding of the underlying aetiological mechanisms could help to establish the diagnosis earlier and allow a more accurate prediction of deformity progression. This, in turn, would prompt imaging and therapeutic intervention at the appropriate time, thereby achieving the best clinical outcome for this group of patients. Cite this article: Bone Joint J2022;104-B(8):915-921.

Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis

In an effort to identify rare alleles associated with adolescent idiopathic scoliosis (AIS) whole-exome sequencing was performed on a discovery cohort of 73 unrelated patients and 70 age-and sex matched controls, all of French-Canadian ancestry. A collapsing gene burden test was performed to analyze rare protein-altering variants using case–control statistics. Since no single gene achieved statistical significance, targeted exon sequencing was performed for 24 genes with the smallest p values, in an independent replication cohort of unrelated severely affected females with AIS and sex-matched controls (N = 96 each). An excess of rare, potentially protein-altering variants was noted in one particular gene, FAT3, although it did not achieve statistical significance. Independently, we sequenced the exomes of all members of a rare multiplex family of three affected sisters and unaffected parents. All three sisters were compound heterozygous for two rare protein-altering variants in FAT3. The parents were single heterozygotes for each variant. The two variants in the family were also present in our discovery cohort. A second validation step was done, using another independent replication cohort of 258 unrelated AIS patients having reach their skeletal maturity and 143 healthy controls to genotype nine FAT3 gene variants, including the two variants previously identified in the multiplex family: p.L517S (rs139595720) and p.L4544F (rs187159256). Interestingly, two FAT3 variants, rs139595720 (genotype A/G) and rs80293525 (genotype C/T), were enriched in severe scoliosis cases (4.5% and 2.7% respectively) compared to milder cases (1.4% and 0.7%) and healthy controls (1.6% and 0.8%). Our results implicate FAT3 as a new candidate gene in the etiology of AIS.

Cerebral White Matter Connectivity in Adolescent Idiopathic Scoliosis: A Diffusion Magnetic Resonance Imaging Study.

Adolescent idiopathic scoliosis (AIS) is characterized by the radiographic presence of a frontal plane curve, with a magnitude greater than 10° (Cobb technique). Diffusion MRI can be employed to assess the cerebral white matter. The aim of this study was to analyze, by means of MRI, the presence of any alteration in the connectivity of cerebral white matter in AIS patients. In this study, 22 patients with AIS participated. The imaging protocol consisted in T1 and diffusion-weighted acquisitions. Based on the information from one of the diffusion acquisitions, a whole brain tractography was performed with the MRtrix tool. Tractography is a method to deduce the trajectory of fiber bundles through the white matter based on the diffusion MRI data. By combining cortical segmentation with tractography, a connectivity matrix of size 84 × 84 was constructed using FA (fractional anisotropy), and the number of streamlines as connectomics metrics. The results obtained support the hypothesis that alterations in cerebral white matter connectivity in patients with adolescent idiopathic scoliosis (AIS) exist. We consider that the application of diffusion MRI, together with transcranial magnetic stimulation neurophysiologically, is useful to search the etiology of AIS.

Aberrant interaction between mutated ADAMTSL2 and LTBP4 is associated with adolescent idiopathic scoliosis.

Adolescent idiopathic scoliosis (AIS) is a complex spinal deformity with a prevalence of 1%-3%. Genetic factors have been associated with the etiology of AIS. However, previous studies mainly focused on common single nucleotide polymorphisms which confer modest disease risk. Recently, rare variants in FBN1 and other extracellular matrix genes have been implicated in AIS, suggesting a potential overlapping disease etiology between AIS and hereditary connective tissue disorders (HCTD). In this study, we systematically analyzed rare variants in a set of HCTD-related genes in 302 AIS patients who underwent exome sequencing. We firstly focused on pathogenic variants based on a monogenic inheritance and identified nine disease-associated variants in FBN1, COL11A1, COL11A2 and TGFBR2. We then explored the potential interactions between variants in different genes based on the case-control statistics. We identified three ADAMTSL2-LTBP4 variant pairs in three AIS patients and none in controls. Furthermore, we revealed that the variant pairs identified in these genes could affect the interaction between ADAMTSL2 and LTBP4 and upregulate TGF-β signaling pathway in human fibroblasts. Our findings implicate that the aberrant interaction between mutated ADAMTSL2 and LTBP4 was associated with AIS.

Prevalence and Significance of Vitamin D Deficiency in Patients Undergoing Corrective Surgery for Adolescent Idiopathic Scoliosis.

The exact etiology of adolescent idiopathic scoliosis (AIS) is unknown, but recently, vitamin D has been suggested to be of importance in the pathophysiology of AIS. This article sought to (1) highlight the prevalence of vitamin D deficiency in patients undergoing corrective surgery for AIS within the United Kingdom and (2) evaluate the correlation and clinical relevance of preoperative back pain with vitamin D deficiency. Data were collected on 201 consecutive patients undergoing corrective surgery for AIS. Baseline data included patient demographics, medical diagnoses, and standing preoperative Cobb angles. All patients had a preoperative 25-hydroxyvitamin D level recorded. One hundred ninety-six patients completed preoperative Scoliosis Research Society-22 outcome scores to quantify preoperative back pain. A total of 177 (89%) patients were young women, and the mean age at time of surgery was 14.9 years (13-18 years). All patients were diagnosed with AIS. The mean Cobb angles at time of surgery was 64°. Only 11 (5.5%) patients had "normal" vitamin D levels (>75 nmol/L), with 147 (74%) patients having deficient levels requiring treatment with supplementation. There was no correlation between vitamin D levels and preoperative Cobb angles (r s = -0.12), and there was a moderate correlation identified between the severity of preoperative vitamin D levels and preoperative back pain scores (r s =0.42). Vitamin D deficiency is common in patients with AIS; however, it is comparable to the national prevalence of vitamin D deficiency in healthy adolescent children. There was a strong correlation between preoperative back pain scores and the severity of vitamin D deficiency. These findings suggest that all patients with AIS should be screened for vitamin D deficiency and that supplementation where appropriate may lead to improved pain scores. If vitamin D is prevelant and if vitamin D deficiency is found to cause back pain, then there is an easy/cheap/safe treatement with supplementation.

RHOA inhibits chondrogenic differentiation of mesenchymal stem cells in adolescent idiopathic scoliosis

ABSTRACT Purpose The etiology of adolescent idiopathic scoliosis (AIS) remains unclear. The chondrogenic differentiation of mesenchymal stem cells (MSCs) is important in AIS, and the Ras homolog gene family member A (RHOA) is associated with chondrogenesis. The purpose of this study was to explore the effect of RHOA on the chondrogenic differentiation of MSCs in AIS. Methods We isolated MSCs from patients with AIS (AIS MSCs) and individuals without AIS (control MSCs). The inhibitor Y27632 was used to inhibit the function of RHOA/ROCK signaling, and plasmid-based overexpression and siRNA-mediated knockdown were used to manipulate RHOA expression. CCK-8 was used to detect cell viability. The phosphorylation levels of LIMK1, MLC2 and cofilin were detected by Western blotting. The mRNA expression of aggrecan, SOX9, and COL2A1 were confirmed using RT-PCR. Immunofluorescence was used to analyze F-actin and collagen II. Alcian blue staining was performed to assess the secretion of glycosaminoglycans (GAGs). Results We found that RHOA was significantly upregulated in AIS MSCs, and the phosphorylation levels of LIMK1, MLC2, and cofilin were increased. The mRNA expressions of aggrecan, SOX9, and COL2A1 were notably reduced in AIS MSCs. However, these effects were abolished by Y27632 treatment and RHOA knockdown in AIS MSCs. In addition, RHOA knockdown in AIS MSCs increased the content of collagen II and GAGs. RHOA overexpression in the control MSCs markedly activated the RHOA/ROCK signaling and decreased the expression of aggrecan, SOX9, and COL2A1, F-actin, and GAGs. Conclusion RHOA regulates the chondrogenic differentiation ability of MSCs in AIS via the RHOA/ROCK signaling pathway and this regulation may involve SOX9.

Lumbopelvic postural differences in adolescent idiopathic scoliosis: A pilot study

BackgroundA primary etiology of adolescent idiopathic scoliosis (AIS) is currently unknown, but poor postural control of the spinal extensor musculature has been identified as an AIS risk factor. Identifiable postural differences would aid in advancing the precise postural behaviors that should be modified during Physiotherapy Scoliosis Specific Exercise (PSSE) to help limit the progression of AIS. Research questionAre there any determinable differences in lumbopelvic posture or range of motion between subjects with AIS and controls? MethodsThis prospective cohort pilot study consisted of 53 subjects (27 AIS and 26 control) aged 11–17 years. Subjects had their lumbopelvic posture assessed and monitored using the ViMove DorsaVi sensor package. All subjects underwent a live assessment to obtain initial lumbopelvic (LP) range of motion (ROM) measurements. Subjects were then monitored while continuing with normal activities of daily living (ADLs) for 12 h. With an alpha level of 0.05, nonparametric analyses were performed for each variable via a Mann-Whitney U-test. ResultsDuring the live assessment, controls exhibited a significantly greater anterior pelvic tilt ROM in the sitting position than the AIS group (p = 0.0433). When compared to female controls, females with AIS had a sitting pelvic tilt ROM that was significantly more retroverted (p = 0.0232) and less anteverted (p = 0.0010). During ADLs, female controls exhibited a higher total number of extension events than their female with AIS (p = 0.0263). These associations did not strengthen with greater spinal deformity. SignificanceThis work demonstrates postural differences between patients with AIS and controls. Further study is necessary to determine why patients with AIS adopt these postures, and if PSSEs can be utilized to limit the progression of AIS.

A Functional SNP in the Promoter of LBX1 Is Associated With the Development of Adolescent Idiopathic Scoliosis Through Involvement in the Myogenesis of Paraspinal Muscles.

Previous studies have shown that LBX1 is associated with adolescent idiopathic scoliosis (AIS) in multiple populations. For the first time, rs1322330 located in the putative promoter region of LBX1 was found significantly associated with AIS in the Chinese population [p = 6.08 × 10–14, odds ratio (OR) = 1.42, 95% confidence interval of 1.03–1.55]. Moreover, the luciferase assay and electrophoretic mobility shift assay supported that the allele A of rs1322330 could down-regulate the expression of LBX1 in the paraspinal muscles of AIS. In addition, silencing LBX1 in the myosatellite cells resulted in significantly inhibited cell viability and myotube formation, which supported an essential role of LBX1 in muscle development of AIS. To summarize, rs1322330 may be a novel functional SNP regulating the expression of LBX1, which was involved in the etiology of AIS possibly via regulation of myogenesis in the paraspinal muscles.

Aetiological process of idiopathic scoliosis: from a normal growing spine into a complex 3D spinal deformity

In more than a century of dedicated research into its aetio-pathogenesis, many attempts have been made to understand the exact cause of idiopathic scoliosis. In the literature, the number of causal theories is overwhelming and the aetiology of adolescent idiopathic scoliosis (AIS) is regarded as ‘multi-factorial’. This overview focusses on recent studies that describe the changes from a normal spinal anatomy into the complex three-dimensional deformation and support the hypothesis that several paediatric deformities are a consequence of the unique way the human spine is biomechanically loaded. This has nothing to do with bipedalism, but with the way gravity and muscle tone translate to the unique sagittal shape of the spine, with its pelvic and lumbar lordosis, and the possibility to simultaneously extend the hips and knees. This leads to three rather than two forces acting continuously on the spine axial, anterior and posterior shear. An excess of anterior shear can result in spondylolisthesis and an excess of axial loading can cause osteochondrotic lesions. Unique for human are posterior shear forces, an excess of these result in decreased rotational stiffness of the involved vertebral segments. Certain sagittal spinal profiles, especially in girls around the pubertal growth spurt, predispose for development of a rotational deformity, as is idiopathic scoliosis. Once the growing spine decompensates into an idiopathic scoliosis, it will follow the right-sided rotational pattern that is already present in the non-scoliotic adolescent spine. The rotational deformation ultimately leads to rotatory lordosis around the apices of the curvatures and has major impact on lung function and quality of life.

A Decade in Review after Idiopathic Scoliosis Was First Called a Complex Trait-A Tribute to the Late Dr. Yves Cotrel for His Support in Studies of Etiology of Scoliosis.

Adolescent Idiopathic Scoliosis (AIS) is a prevalent and important spine disorder in the pediatric age group. An increased family tendency was observed for a long time, but the underlying genetic mechanism was uncertain. In 1999, Dr. Yves Cotrel founded the Cotrel Foundation in the Institut de France, which supported collaboration of international researchers to work together to better understand the etiology of AIS. This new concept of AIS as a complex trait evolved in this setting among researchers who joined the annual Cotrel meetings. It is now over a decade since the first proposal of the complex trait genetic model for AIS. Here, we review in detail the vast information about the genetic and environmental factors in AIS pathogenesis gathered to date. More importantly, new insights into AIS etiology were brought to us through new research data under the perspective of a complex trait. Hopefully, future research directions may lead to better management of AIS, which has a tremendous impact on affected adolescents in terms of both physical growth and psychological development.

The Susceptibility and Potential Functions of the LBX1 Gene in Adolescent Idiopathic Scoliosis.

Genome-wide association studies have identified many susceptibility genes for adolescent idiopathic scoliosis (AIS). However, most of the results are hard to be replicated in multi-ethnic populations. LBX1 is the most promising candidate gene in the etiology of AIS. We aimed to appraise the literature for the association of LBX1 gene polymorphisms with susceptibility and curve progression in AIS. We also reviewed the function of the LBX1 gene in muscle progenitor cell migration and neuronal determination processes. Three susceptibility loci (rs11190870, rs625039, and rs11598564) near the LBX1 gene, as well as another susceptibility locus (rs678741), related to LBX1 regulation, have been successfully verified to have robust associations with AIS in multi-ethnic populations. The LBX1 gene plays an essential role in regulating the migration and proliferation of muscle precursor cells, and it is known to play a role in neuronal determination processes, especially for the fate of somatosensory relay neurons. The LBX1 gene is the most promising candidate gene in AIS susceptibility due to its position and possible functions in muscle progenitor cell migration and neuronal determination processes. The causality between susceptibility loci related to the LBX1 gene and the pathogenesis of AIS deserves to be explored with further integrated genome-wide and epigenome-wide association studies.

Coding Variants Coupled With Rapid Modeling in Zebrafish Implicate Dynein Genes, dnaaf1 and zmynd10, as Adolescent Idiopathic Scoliosis Candidate Genes.

Adolescent idiopathic scoliosis (AIS) is the most common pediatric spine disorder affecting ∼3% of children worldwide. Human genetic studies suggest a complex polygenic disease model for AIS with large genetic and phenotypic heterogeneity. However, the overall genetic etiology of AIS remains poorly understood. To identify additional AIS susceptibility loci, we performed whole-exome sequencing (WES) on a cohort of 195 Southern Chinese AIS patients. Bioinformatics analysis identified 237 novel rare variants associated with AIS, located in 232 new susceptibility loci. Enrichment analysis of these variants revealed 10 gene families associated with our AIS cohort. We screened these gene families by comparing our candidate gene list with IS candidate genes in the Human Phenotype Ontology (HPO) database and previous reported studies. Two candidate gene families, axonemal dynein and axonemal dynein assembly factors, were retained for their associations with ciliary architecture and function. The damaging effects of candidate variants in dynein genes dnali1, dnah1, dnaaf, and zmynd10, as well as in one fibrillin-related gene tns1, were functionally analyzed in zebrafish using targeted CRISPR/Cas9 screening. Knockout of two candidate genes, dnaaf1 or zmynd10, recapitulated scoliosis in viable adult zebrafish. Altogether, our results suggest that the disruption of one or more dynein-associated factors may correlate with AIS susceptibility in the Southern Chinese population.

From genetics to epigenetics to unravel the etiology of adolescent idiopathic scoliosis.

Scoliosis is defined as the three-dimensional (3D) structural deformity of the spine with a radiological lateral Cobb angle (a measure of spinal curvature) of ≥10° that can be caused by congenital, developmental or degenerative problems. However, those cases whose etiology is still unknown, and affect healthy children and adolescents during growth, are the commonest form of spinal deformity, known as adolescent idiopathic scoliosis (AIS). In AIS management, early diagnosis and the accurate prediction of curve progression are most important because they can decrease negative long-term effects of AIS treatment, such as unnecessary bracing, frequent exposure to radiation, as well as saving the high costs of AIS treatment. Despite efforts made to identify a method or technique capable of predicting AIS progression, this challenge still remains unresolved. Genetics and epigenetics, and the application of machine learning and artificial intelligence technologies, open up new avenues to not only clarify AIS etiology, but to also identify potential biomarkers that can substantially improve the clinical management of these patients. This review presents the most relevant biomarkers to help explain the etiopathogenesis of AIS and provide new potential biomarkers to be validated in large clinical trials so they can be finally implemented into clinical settings.