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 extracellular matrix, cilia, and actin networks, but the genetic architecture and underlying mechanisms remain unresolved. Here, we used whole‐exome sequencing from three affected individuals in a multigenerational family with IS and identified 19 uncommon variants (minor allele frequency < 0.05). Genotyping of additional family members identified a candidate heterozygous variant (H1115Q, G>C, rs142032413) within the ciliary gene KIF7, a regulator within the hedgehog (Hh) signaling pathway. Resequencing of the 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 study suggests defects in KIF7‐dependent Hh signaling, which may drive pathogenesis in a subset of individuals with IS.

中文翻译：

---

KIF7 突变与人类特发性脊柱侧凸和斑马鱼轴向弯曲有关

特发性脊柱侧凸 (IS) 是一种脊柱疾病，影响多达 3% 的其他健康儿童。IS具有很强的家族遗传成分，并且由于表型和遗传力的显着变异性而被认为具有遗传复杂性。以前的研究确定了可能导致 IS 易感性的假定基因座和变体，包括在细胞外基质、纤毛和肌动蛋白网络中，但遗传结构和潜在机制仍未解决。在这里，我们使用来自多代 IS 家族中三个受影响个体的全外显子组测序，并确定了 19 个不常见的变异（次要等位基因频率 < 0.05）。其他家族成员的基因分型确定了睫状基因 KIF7 内的候选杂合变体（H1115Q，G>C，rs142032413），刺猬（Hh）信号通路中的调节剂。第二组不相关的 IS 个体和对照的重新测序仅在受影响的个体中发现了 KIF7 的几个严重突变。随后，我们生成了一个突变斑马鱼模型kif7使用 CRISPR-Cas9。kif7 ^co63/co63斑马鱼表现出严重的脊柱侧弯，在幼鱼中出现并在成年期出现。我们观察到kif7 ^co63/co63胚胎的大脑、Reissner 纤维或中央管纤毛没有畸形，尽管在 Hh 通路基因表达中观察到了改变。这项研究表明 KIF7 依赖性 Hh 信号传导存在缺陷，这可能会驱动一部分 IS 个体的发病机制。