BACKGROUND & AIMS:
BACKGROUND:Klippel-Feil syndrome (KFS) represents a rare anomaly characterized by congenital fusion of the cervical vertebrae. The underlying molecular etiology remains largely unknown because of the genetic and phenotypic heterogeneity.
METHODS:We consecutively recruited a Chinese cohort of 37 patients with KFS. The clinical manifestations and radiological assessments were analyzed and whole-exome sequencing (WES) was performed. Additionally, rare variants in KFS cases and controls were compared using genetic burden analysis.
RESULTS:We primarily examined rare variants in five reported genes (GDF6, MEOX1, GDF3, MYO18B and RIPPLY2) associated with KFS and detected three variants of uncertain significance in MYO18B. Based on rare variant burden analysis of 96 candidate genes related to vertebral segmentation defects, we identified BAZ1B as having the highest probability of association with KFS, followed by FREM2, SUFU, VANGL1 and KMT2D. In addition, seven patients were proposed to show potential oligogenic inheritance involving more than one variants in candidate genes, the frequency of which was significantly higher than that in the in-house controls.
CONCLUSIONS:Our study presents an exome-sequenced cohort and identifies five novel genes potentially associated with KFS, extending the spectrum of known mutations contributing to this syndrome. Furthermore, the genetic burden analysis provides further evidence for potential oligogenic inheritance of KFS.
背景与目标:
背景:Klippel-Feil综合征(KFS)代表一种罕见的异常,其特征是先天性颈椎融合。由于遗传和表型的异质性,潜在的分子病因仍是未知之数。
方法:我们连续招募了37例KFS患者的中国队列。分析了临床表现和放射学评估,并进行了全外显子测序(WES)。此外,使用遗传负担分析比较了KFS病例和对照中的罕见变异。
结果:我们主要检查了与KFS相关的五个报告基因(GDF6,MEOX1,GDF3,MYO18B和RIPPLY2)中的稀有变异体,并检测到MYO18B中三个具有不确定意义的变异体。基于对与椎骨节段缺陷相关的96个候选基因的罕见变异负荷分析,我们确定BAZ1B与KFS关联的可能性最高,其次是FREM2,SUFU,VANGL1和KMT2D。此外,提议了7名患者表现出潜在的寡聚遗传,涉及候选基因中的一种以上变异,其发生频率显着高于内部对照中的变异。
结论:我们的研究提出了一个外显子组测序队列,并鉴定了可能与KFS相关的五个新基因,从而扩展了导致该综合征的已知突变的范围。此外,遗传负担分析为KFS的潜在寡聚遗传提供了进一步的证据。