Table 4_Comprehensive genetic screening of 70 severe adolescent idiopathic scoliosis probands reveals novel pathogenic variants and syndromic associations.xlsx

IntroductionIdiopathic scoliosis (IS) is a complex spinal deformity affecting ~3% of the population, with a multifactorial and genetically heterogeneous origin. This study aimed to investigate the genetic origins of severe IS by examining both constitutional and post-zygotic alterations.
MethodsWe analyzed 70 unrelated IS-affected individuals using whole exome sequencing (WES) and SNP array approaches on intraoperatively collected articular processes and blood samples.
ResultsTwo pathogenic constitutional copy number variants (CNVs) were identified – a 43.6 Mb duplication on chromosome 8p and trisomy X – along with eight regions of homozygosity (ROH) located on chromosomes 1, 2, 8, 12, 14, and 16, absent in ethnically matched controls. Additionally, a heterozygous DMD deletion (exons 17–36) was found in one female, and rare recurrent pathogenic single-nucleotide variants (SNVs) were detected in ENAM and FLNB genes. Notably, 13% (95% CI, 6.1–23%) of individuals harbored pathogenic variants, spanning CNVs, ROH, and SNVs, suggesting a genetic contribution to IS.
DiscussionOur findings demonstrate that one in seven cases classified as idiopathic may have an underlying monogenic cause. This study underscores the polygenic and heterogeneous nature of IS and highlights the need for genetic testing by integrating WES and SNP array analyses into its diagnostic workflow. Our findings suggest that incorporating genetic testing into the diagnostic evaluation of severe IS patients may enable personalized genetic counseling and, consequently, improve clinical management.

引言
特发性脊柱侧凸（Idiopathic Scoliosis, IS）是一种复杂的脊柱畸形，累及约3%的人群，其发病机制为多因素且具有遗传异质性。本研究旨在通过检测胚系及合子后变异，探究重度特发性脊柱侧凸的遗传起源。

方法
本研究纳入70名无亲缘关系的特发性脊柱侧凸患者，对术中采集的关节突组织及血液样本进行全外显子测序（Whole Exome Sequencing, WES）与单核苷酸多态性（Single Nucleotide Polymorphism, SNP）芯片检测。

结果
本研究共检出2个致病性胚系拷贝数变异（Copy Number Variant, CNV）：8号染色体短臂（8p）上43.6 Mb的片段重复，以及X染色体三体；同时发现8个纯合子区域（Regions of Homozygosity, ROH），分布于1、2、8、12、14及16号染色体，上述区域在种族匹配的对照人群中未出现。此外，1名女性患者携带DMD基因杂合缺失（外显子17-36），同时在ENAM与FLNB基因中检测到罕见的复发性致病性单核苷酸变异（Single-Nucleotide Variant, SNV）。值得注意的是，13%的患者（95%置信区间：6.1%~23%）携带致病性变异，涵盖拷贝数变异、纯合子区域及单核苷酸变异，提示遗传因素在特发性脊柱侧凸的发病中发挥作用。

讨论
本研究结果显示，每7例被归类为特发性脊柱侧凸的患者中，即有1例可能存在单基因致病基础。本研究明确了特发性脊柱侧凸的多基因性与遗传异质性，并强调需将全外显子测序与SNP芯片检测整合至诊断流程中，以开展遗传检测。本研究结果提示，将遗传检测纳入重度特发性脊柱侧凸患者的诊断评估流程，可实现个体化遗传咨询，进而优化临床诊疗管理。