Liu Ziwei, Zhou Ding, Wang Chunli, Zheng Bixia, Yan Qing, Zhou Wei, Wang Gang
Department of Neurosurgery, Children's Hospital of Nanjing Medical University, Nanjing, China.
Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.
Mol Genet Genomic Med. 2025 May;13(5):e70106. doi: 10.1002/mgg3.70106.
Craniosynostosis (CS), a heterogeneous craniofacial disorder caused by premature fusion of cranial sutures, is sub-classified anatomically by suture involvement (sagittal, metopic, coronal, lambdoid) and phenotypically into isolated/non-syndromic forms or syndromic (CS with extracranial anomalies). Pathogenic variants in multiple genetic loci have been implicated in CS, with particular significance attributed to allelic variants in IL11RA (interleukin-11 receptor alpha subunit; OMIM#600939). Clinical observations of individuals with IL11RA mutations indicate syndromic CS, characterized by dental anomalies and Crouzon-like facial features.
Genetic analyses were carried out utilizing whole-exome sequencing, with subsequent validation through direct Sanger sequencing. IL11RA biallelic pathogenic variants were detected and further analyzed by multiple in silico prediction tools, including 3D protein modeling.
Our cohort comprises six pediatric patients presenting with CS linked to biallelic pathogenic mutations in IL11RA, including two previously unreported variants (p.Pro218Argfs*140, p.Trp132Ter). Three-dimensional protein structure modeling and molecular docking simulations demonstrated that four missense variants (p.Pro116Leu, p.Glu126Gly, p.Gly231Val, p.Leu236Pro) disrupt hydrogen bond networks critical for maintaining the IL-11 receptor alpha subunit's tertiary structure, significantly reducing ligand-binding affinity to both interleukin-11 (IL-11) and gp130.
This study describes the clinical phenotype of six children with craniosynostosis and reveals novel variants in the IL11RA gene, thereby broadening the genotypic spectrum associated with this gene. Given the scarcity of patients reported in the literature, a detailed examination of the specific clinical and molecular characteristics will benefit our understanding of craniosynostosis caused by IL11RA variants.
颅缝早闭（CS）是一种由颅缝过早融合引起的异质性颅面疾病，根据受累颅缝（矢状缝、额缝、冠状缝、人字缝）在解剖学上进行分类，并在表型上分为孤立性/非综合征型或综合征型（伴有颅外异常的CS）。多个基因位点的致病变异与CS有关，其中IL11RA（白细胞介素-11受体α亚基；OMIM#600939）的等位基因变异具有特殊意义。对携带IL11RA突变个体的临床观察表明为综合征型CS，其特征为牙齿异常和克鲁宗样面部特征。
利用全外显子测序进行基因分析，随后通过直接桑格测序进行验证。检测到IL11RA双等位基因致病变异，并通过多种计算机预测工具（包括三维蛋白质建模）进行进一步分析。
我们的队列包括6名患有与IL11RA双等位基因致病变异相关的CS的儿科患者，包括2个先前未报道的变异（p.Pro218Argfs*140，p.Trp132Ter）。三维蛋白质结构建模和分子对接模拟表明，4个错义变异（p.Pro116Leu、p.Glu126Gly、p.Gly231Val、p.Leu236Pro）破坏了维持白细胞介素-11受体α亚基三级结构至关重要的氢键网络，显著降低了对白细胞介素-11（IL-11）和gp130的配体结合亲和力。
本研究描述了6名颅缝早闭儿童的临床表型，并揭示了IL11RA基因中的新变异，从而拓宽了与该基因相关的基因型谱。鉴于文献报道的患者稀缺，详细检查特定的临床和分子特征将有助于我们了解由IL11RA变异引起的颅缝早闭。
