Whole-exome sequencing identified a de novo variant of the AT-hook DNA-binding motif-containing protein 1 gene in a Chinese patient with Xia-Gibbs syndrome

AbstractObjective: This study investigated the genetic pathogenesis, clinical features, brain function, and neurobehavioral features of a Xia-Gibbs syndrome (XGS) pedigree.Methods:Candidate variants in the patient and his pedigree were indentified using whole-exome sequencing and Sanger sequencing.The patient's genetic and clinical features were analyzed referencing his pedigree and the literature.Brain dysfunction was evaluated using functional magnetic resonance imaging(fMRI).Resules:The patient carried a de novo variant c.3259dupT(p.Glu1087fs)in the AT-hook DNA-binging motif-containing protein 1 gene(AHDC1).The literature review indicated that the patient exhibited the typical features of XGS,including systemic developmental delay,hypotonia,intellectual disability,obstructive sleep apnea with snoring,and mild facial deformity.The patient demonstrated no behavioral abnormalities.The literature did not mention abnormal development of the fifth phalanx(single dermatoglyphic pattern),which was the patient's distinctive clinical feature.The fMRI diffusion tensor imaging sequences used the corpus callosum,brain stem,and frontosuboccipital tracts as the regions of interest (ROI) to track fiber bundles,which were sparse in all ROI.Resting-state fMRI was performed using the posterior cingulate cortex as the ROI to analyze its functional connectivity.Conclusion:This study determined that a XGS case was caused by a previously unreported c.3259dupT(p.Glu1087fs) mutation in the AHDC1 gene.Our findings expand the genotype and phenotype spectrum of XGS,which will guide genetic counseling and management of patients with this disease.Keywords:AHDC1 gene;whole-exome sequencing;brain functional magnetic resonance imaging;clinical phenotype;genotype

摘要：
研究目的：本研究针对一例夏-吉布斯综合征（Xia-Gibbs Syndrome, XGS）家系，探究其遗传发病机制、临床特征、脑功能及神经行为学特征。
研究方法：采用全外显子测序（whole-exome sequencing）与Sanger测序（Sanger sequencing）对患者及其家系的候选变异进行鉴定；结合家系资料与文献报道分析患者的遗传与临床特征；采用功能磁共振成像（functional magnetic resonance imaging, fMRI）评估脑功能异常。
研究结果：患者在AT钩状DNA结合基序包含蛋白1基因（AT-hook DNA-binding motif-containing protein 1 gene, AHDC1）中携带新发变异c.3259dupT(p.Glu1087fs)。文献调研显示，患者表现出XGS的典型特征，包括全面性发育迟缓、肌张力低下、智力障碍、打鼾伴阻塞性睡眠呼吸暂停，以及轻度面部畸形。患者未出现行为异常。本次研究发现患者存在一项此前文献未提及的独特临床特征——第五指（趾）单褶皮纹发育异常。本研究采用功能磁共振成像扩散张量成像序列，以胼胝体、脑干及额枕束作为感兴趣区（regions of interest, ROI）进行纤维束追踪，结果显示所有感兴趣区内的纤维束均较为稀疏；采用静息态功能磁共振成像，以后扣带回作为感兴趣区分析其功能连接特性。
研究结论：本研究确认一例XGS病例由AHDC1基因中此前未被报道的c.3259dupT(p.Glu1087fs)突变所致。本研究拓展了XGS的基因型与表型谱，可为该疾病的遗传咨询与临床管理提供指导。
关键词：AHDC1基因；全外显子测序；脑功能磁共振成像；临床表型；基因型