Table1_A novel homozygous RSPH4A variant in a family with primary ciliary dyskinesia and literature review.DOCX

Introduction: Primary ciliary dyskinesia (PCD) is a rare heterogeneous disease caused by abnormalities in motile cilia. In this case report, we first analyzed the clinical and genetic data of a proband who was suspected of having PCD on the basis of her clinical and radiological findings.
Methods: Whole-exome sequencing was performed, and a variant in the RSPH4A gene was identified in the proband. Sanger sequencing was used for validation of RSPH4A variants in the proband, her sister, her daughter and her parents. Finally, the phenotypic features of the patient were analyzed, and the current literature was reviewed to better understand the gene variants in PCD related to hearing loss and the clinical manifestations of the RSPH4A variant in PCD.
Results: The chief clinical symptoms of this proband included gradual mixed hearing loss, otitis media, anosmia, sinusitis, recurrent cough and infertility. Her DNA sequencing revealed a novel homozygous T to C transition at position 1321 within exon 3 of RSPH4A according to genetic testing results. This variant had never been reported before. The homozygous variant resulted in an amino acid substitution of tryptophan by arginine at position 441 (p.Trp441Arg). The same variant was also found in the proband’s sister, and a heterozygous pathogenic variant was identified among immediate family members, including the proband’s daughter and parents.
Discussion: A literature review showed that 16 pathogenic variants in RSPH4A have been reported. Hearing loss had only been observed in patients with the RSPH4A (c.921+3_6delAAGT) splice site mutation, and the specific type of hearing loss was not described.

引言：原发性纤毛运动障碍（Primary ciliary dyskinesia, PCD）是一种由运动性纤毛异常引发的罕见异质性疾病。本病例报告中，我们首先对1名依据临床及影像学表现疑似罹患PCD的先证者的临床与遗传学数据进行了分析。

方法：本研究实施了全外显子测序（Whole-exome sequencing），在先证者体内检出RSPH4A基因存在变异。采用Sanger测序（Sanger sequencing）对先证者、其姐妹、女儿及父母体内的RSPH4A基因变异进行验证。最后，我们分析了该患者的表型特征，并复习了当前相关文献，以更好地了解PCD中与听力损失相关的基因变异，以及RSPH4A变异在PCD中的临床表现。

结果：该先证者的主要临床症状包括渐进性混合性听力损失、中耳炎、嗅觉缺失、鼻窦炎、反复咳嗽及不孕症。遗传学检测结果显示，其DNA测序发现RSPH4A基因第3外显子1321位点存在一种全新的纯合T→C转换变异，该变异此前未见报道。此纯合变异导致第441位色氨酸被精氨酸取代（p.Trp441Arg）。先证者的姐妹体内也检出了相同变异，其直系亲属（包括先证者的女儿与父母）体内均检出杂合致病性变异。

讨论：文献复习结果显示，目前已有16种RSPH4A基因致病性变异被报道。仅在携带RSPH4A基因（c.921+3_6delAAGT）剪接位点突变的患者中观察到听力损失，且未对该听力损失的具体类型进行描述。