CEP135变异导致先天性小头畸形和原发性纤毛运动障碍

文献信息

中文摘要

引言： 原发性纤毛运动障碍（PCD）是一种运动纤毛功能障碍性疾病，可引起慢性呼吸道感染，也可能罕见地表现为非运动纤毛功能障碍的某些方面，包括视网膜炎、中枢神经系统畸形、骨骼发育不良和感音神经性听力损失。然而，先天性小头畸形此前尚未与PCD相关联。
方法： 我们发现了三名患有先天性小头畸形和符合PCD的慢性呼吸道疾病的儿童。进行了全面的PCD诊断检测和全外显子组测序。对扩增和再生长后的鼻上皮细胞进行了表征，包括逆转录聚合酶链反应、高速视频显微镜检查以及新遗传变异的转录本分析。
结果： 来自两个家庭的三例儿科病例因CEP135的常染色体隐性变异而患有原发性小头畸形。所有病例均表现出慢性化脓性呼吸道症状、复发性中耳炎和支气管扩张，且鼻一氧化氮水平低。一例具有致病性复合杂合功能丧失变异，而另外两例具有同义不确定意义变异。对CEP135不确定意义变异的转录本分析支持剪接缺陷为致病原因。再生长的鼻上皮细胞显示整体纤毛超微结构正常，但全长轴丝数量减少。纤毛搏动模式严重异常，并且在细胞再生长前后均发现远端轴丝肿胀伴球状尖端结构。
结论： 这些病例确立了CEP135变异是伴小头畸形的PCD的一种新病因。球状纤毛尖端的TEM发现可能是运动和非运动纤毛功能障碍重叠纤毛病患者的可靠标志物。

英文摘要

INTRODUCTION: Primary ciliary dyskinesia (PCD), a disorder of motile ciliary dysfunction causing chronic respiratory infections, may also rarely present with aspects of non-motile ciliary dysfunction, including retinitis, central nervous system malformations, skeletal dysplasia, and sensorineural hearing loss. However, congenital microcephaly has not been previously associated with PCD.
METHODS: We identified three children with congenital microcephaly and chronic respiratory disease consistent with PCD. Comprehensive PCD diagnostic testing and whole exome sequencing were performed. Characterization of nasal epithelial cells after expansion and regrowth included reverse transcription polymerase chain reaction, high speed videomicroscopy, and transcript analysis of novel genetic variants.
RESULTS: Three pediatric cases from two families had primary microcephaly from autosomal recessive variants in CEP135. All cases displayed chronic suppurative respiratory symptoms, recurrent otitis media, and bronchiectasis with low nasal nitric oxide. One case had pathogenic, compound heterozygous, loss of function variants, while the other two cases had homozygous variants of uncertain significance. Transcript analyses of CEP135 variants of uncertain significance supported a splicing defect as disease-causing. Regrown nasal epithelial cells demonstrated overall normal ciliary ultrastructure with decreased numbers of full-length axonemes. Ciliary beat pattern was grossly abnormal, and distal axoneme swelling with bulbous-tip structures were identified pre- and post-cellular regrowth.
CONCLUSION: These cases establish variants in CEP135 as a novel cause of PCD with microcephaly. The TEM findings of bulbous ciliary tips may be a reliable marker of overlapping ciliopathies in patients with aspects of motile and non-motile ciliary dysfunction.