Exploring the association between specific genes and the onset of idiopathic scoliosis: a systematic review

Abstract

Background Idiopathic Scoliosis (IS) is the most common spinal deformity in adolescents, accounting for 80% of all spinal deformities. However, the etiology remains uncertain in most cases, being identified as Adolescent Idiopathic Scoliosis (AIS). IS treatments range from observation and sport to bracing or surgery. Several risk factors including sex and familiarity, have been linked with IS. Although there are still many uncertainties regarding the cause of this pathology, several studies report a greater incidence of the defect in families in which at least one other first degree relative is affected. This study systematically reviews the available literature to identify the most significant genes or variants related to the development and onset of IS. Methods The research question was formulated using a PIOS approach on the following databases: Medline, Embase, Cinahl, Scopus, Web of Science and Google Scholar. The search was performed from July to August 2021, and articles from the inception of the database to August 2021 were searched. Results 24 of the 919 initially identified studies were included in the present review. The 24 included studies observed a total of 16,316 cases and 81,567 controls. All the considered studies stated either the affected gene and/or specific SNPs. CHD7, SH2B1, ESR, CALM1, LBX1, MATN1, CHL1, FBN1 and FBN2 genes were associated with IS development. Conclusions Although association can be found in some candidate genes the field of research regarding genetic association with the onset of IS still requires more information.

The Whole-Exome Sequencing of a Cohort of 19 Families with Adolescent Idiopathic Scoliosis (AIS): Candidate Pathways

“…The more noticeable clinical studies on AIS patients and calmodulin were conducted by Lowe et al [36], who discovered that platelet calmodulin levels had then been sampled in AIS patients and correlate closely with curve progression, and by Marcucio et al and Zhao et al [37,38], who both found different levels of calmodulin in the paraspinal muscles (convex and concave sides) of AIS patients. CALM-1 (calmodulin 1) variants have been found to be associated with AIS in several cohorts [10,39,40]. In addition, the melatonin-calmodulin interactions involve cytoskeleton, filamentous actin and microtubule assembly, which have been shown by Miller et al to be key factors in AIS physiopathology [19,41,42].…”

“…The biomechanical/musculoskeletal theory hypotheses that the cartilage, bone and/or muscle are subject to disequilibrium during growth, resulting in the three-dimensional deformity of the spine. FBN1 (fibrillin-1, a component of the extracellular matrix), MATN1 (matrilin-1, a cartilage protein) and LBX1 (ladybird homeaobox-1, a regulator of muscle precursor cell migration) have been identified as the most promising candidate genes related to the musculoskeletal theory [9][10][11]. The hormonal theory states that a dysfunction in hormones regulating bone formation (such as estrogen), promoting osteoblast proliferation (such as melatonin) or regulating bone formation (such as leptin) may also induce disequilibrium in spine growth, resulting in AIS.…”

“…The hormonal theory states that a dysfunction in hormones regulating bone formation (such as estrogen), promoting osteoblast proliferation (such as melatonin) or regulating bone formation (such as leptin) may also induce disequilibrium in spine growth, resulting in AIS. Variants in CALM1 and ESR1 have been found to be associated with AIS in previous studies [10,12]. The recent progress in the field of genetics has allowed family-based studies and GWAS (Genome-Wide Association Study) in scoliosis cohorts.…”

Sex differences in musculoskeletal injury and disease risks across the lifespan: Are there unique subsets of females at higher risk than males for these conditions at distinct stages of the life cycle?

“…In addition, it is not known whether in detail whether the muscle involvement is primary or secondary regarding causality. To address some of the gaps, a number of studies and reviews have explored and analyzed the possibility that there are genetic or epigenetic-related variables at play in disease initiation and progression ( Gorman et al, 2012 ; Zaydman et al, 2021 ; De Salvatore et al, 2022 ; Faldini et al, 2022 ). A number of studies have implicated a variety of genes and gene families in AIS including Fibrillin-1 ( Sheng et al, 2019 ; De Azevedo et al, 2022 ), Fibrillin-1 and Fibrillin-2 variants associated with severe disease ( Buchan et al, 2014 ), estrogen receptor variants and polymorphisms ( Esposito et al, 2009 ; Wang et al, 2020 ), the NUCKS1 gene in Chinese adolescents ( Xu et al, 2017 ), and the helicase DNA-binding protein 7 (CHD7) ( Wu et al, 2021 ; Wu et al, 2022 ).…”

Association of LBX1 Gene Methylation Level with Disease Severity in Patients with Idiopathic Scoliosis: Study on Deep Paravertebral Muscles

“…IS is a multifactorial disease with an important genetic background, probably modulated by environmental factors, which are claimed to impact IS occurrence or progression [ 4 ]. Although many genetic studies concerning the IS genetic background have been conducted and several target genes suggested, most of them have not been confirmed in replication studies [ 5 , 6 , 7 , 8 ].…”