Idiopathic scoliosis (IS) is a spinal disorder affecting up to 3% of otherwise healthy children. IS has a strong familial genetic component and is believed to be genetically complex due to significant variability in phenotype and heritability. Previous studies identified putative loci and variants possibly contributing to IS susceptibility, including within ECM, cilia and actin networks, but the genetic architecture and underlying mechanisms remains unresolved. Here, we used whole exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (MAF C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of a second cohort of unrelated IS individuals and controls identified several severe mutations in KIF7 in affected individuals only. Subsequently, we generated a mutant zebrafish model of kif7 using CRISPR‐Cas9. kif7^co63/co63 zebrafish displayed severe scoliosis, presenting in juveniles and progressing through adulthood. We observed no deformities in the brain, Reissner fiber, or central canal cilia in kif7^co63/co63 embryos, although alterations were seen in Hh pathway gene expression. This research suggests defects in KIF7‐dependent Hh signaling may drive pathogenesis in a subset of individuals with IS.

Adolescent idiopathic scoliosis (AIS) is a lateral spinal curvature >10° with rotation that affects 2–3% of healthy children across populations. AIS is known to have a significant genetic component, and despite a handful of risk loci identified in unrelated individuals by GWAS and next-generation sequencing methods, the underlying etiology of the condition remains largely unknown. In this study, we performed exome sequencing of affected individuals within 23 multigenerational families, with the hypothesis that the occurrence of rare, low frequency, disease-causing variants will co-occur in distantly related, affected individuals. Bioinformatic filtering of uncommon, potentially damaging variants shared by all sequenced family members revealed 1448 variants in 1160 genes across the 23 families, with 132 genes shared by two or more families. Ten genes were shared by >4 families, and no genes were shared by all. Gene enrichment analysis showed an enrichment of variants in cytoskeletal and extracellular matrix related processes. These data support a model that AIS is a highly polygenic disease, with few variant-containing genes shared between affected individuals across different family lineages. This work presents a novel resource for further exploration in familial AIS genetic research.

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.

Systematic reviews hold immense promise as tools to highlight evidence-based practices that can reduce or aim to eliminate racial health disparities. Currently, consensus on centering racial health equity in systematic reviews and other evidence synthesis products is lacking. Centering racial health equity implies concentrating or focusing attention on health equity in ways that bring attention to the perspectives or needs of groups that are typically marginalized. This Cochrane US Network team and colleagues, with the guidance of a steering committee, sought to understand the views of varied interest holders through semistructured interviews and conducted evidence syntheses addressing (1) definitions of racial health equity, (2) logic models and frameworks to centering racial health equity, (3) interventions to reduce racial health inequities, and (4) interest holder engagement in evidence syntheses. Our methods and teams include a primarily American and Canadian lens; however, findings and insights derived from this work are applicable to any region in which racial or ethnic discrimination and disparities in care due to structural causes exist. In this series, we explain why centering racial health equity matters and what gaps exist and may need to be prioritized. The interviews and systematic reviews identified numerous gaps to address racial health equity that require changes not merely to evidence synthesis practices but also to the underlying evidence ecosystem. These changes include increasing representation, establishing foundational guidance (on definitions and causal mechanisms and models, building a substantive evidence base on racial health equity, strengthening methods guidance, disseminating and implementing results, and sustaining new practices). Centering racial health equity requires consensus on the part of key interest holders. As part of the next steps in building consensus, the manifold gaps identified by this series of papers need to be prioritized. Given the resource constraints, changes in norms around systematic reviews are most likely to occur when evidence-based standards for success are clearly established and the benefits of centering racial health equity are apparent. Racial categories are not based on biology, but racism has negative biological effects. People from racial or ethnic minority groups have often been left out of research and ignored in systematic reviews. Systematic reviews often help clinicians and policymakers with evidence-based decisions. Centering racial health equity in systematic reviews will help clinicians and policymakers to improve outcomes for people from racial or ethnic minority groups. We conducted interviews and a series of four systematic reviews on definitions, logic models and frameworks, methods, interventions, and interest-holder engagement in syntheses. We found that much work remains to be done in centering racial health equity in systematic reviews. Specifically, systematic reviewers need to change who is represented on their teams, establish foundational guidance (on definitions and causal mechanisms and models, identify what interventions work to address racial health equity, strengthen method guidance, disseminate and implement results, and sustain new practices).

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere’s disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere’s disease, and 38 European–American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere’s disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease.