Evidence map›Paper›PMID 39764684›Full record

ArticleMolecular genetics & genomic medicine2025

Interpreting Variants of Uncertain Significance in PCD: Abnormal Splicing Caused by a Missense Variant of DNAAF3.

Haixia Zheng, Chongsheng Cheng, Miao He, Wangji Zhou, Yixuan Li, Jinrong Dai, Ting Zhang, Kai-Feng Xu, Xue Zhang, Xinlun Tian and 1 more

Abstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular genetics & genomic medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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0cells of the map it votes in
1citing papers in PubMed
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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

11 authors.

Haixia ZhengMcKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Chongsheng ChengDepartment of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Miao HeMcKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Wangji ZhouDepartment of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Yixuan LiMcKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Jinrong DaiDepartment of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Ting ZhangDepartment of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Kai-Feng XuDepartment of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Xue ZhangMcKusick-Zhang Center for Genetic Medicine, State Key Laboratory for Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Xinlun TianDepartment of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Yaping LiuThe State Key Laboratory for Complex Severe and Rare Diseases, the State Key Sci-Tech Infrastructure for Translational Medicine, Peking Union Medical College Hospital, Beijing, China.ORCID https://orcid.org/0000-0001-8274-7674

Funding

CAMS Innovation Fund for Medical Sciences 2021-I2M-1-018National High Level Hospital Clinical Research Funding 2023-PUMCH-E-012National Key Research and Development Program of China 2022YFC2703900National Natural Science Foundation of China 82394420National Natural Science Foundation of China 82394423The National Natural Science Foundation of China 82370056 CAMS Innovation Fund for Medical Sciences (CIFMS) 2023-I2M-C&T-A-002
6 · The paper itself

Abstract

backgroundPrimary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by dysfunction of motile cilia. While approximately 50 genes have been identified, around 25% of PCD patients remain genetically unexplained; elucidating the pathogenicity of specific variants remains a challenge.

methodsWhole exome sequencing (WES) and Sanger sequencing were conducted to identify potential pathogenic variants of PCD. Minigene assays were performed to evaluate the pathogenicity of variants. Transmission electron microscopy (TEM) and high-speed video analysis (HSVA) were conducted to analyze the function of cilia in respiratory epithelial cells.

resultsWe identified two variants of DNAAF3: c.557G>A, p.G186E in exon 5, and c.1364G>A, p.G455D at the terminal nucleotide of exon 10 in a 16-year-old male patient. Through a minigene assay, we demonstrated that the c.1364G>A variant led to a four-nucleotide skipping. The cilia in epithelial ciliary cells of the proband were almost immotile. The absence of outer dynein arms and inner dynein arms was also observed.

conclusionsOur study identified two compound heterozygous variants of DNAAF3, a pathogenic gene for PCD, and proved that a novel missense variant c.1364G>A affects splicing. Our findings not only expanded the spectrum of mutations in the DNAAF3 gene but also highlighted the importance of investigating variants of uncertain significance (VUS) for comprehensive genetic diagnoses.

Indexed as

Mutation, MissenseRNA SplicingAdolescentCiliaCiliary Motility DisordersHumansKartagener SyndromeMaleDNAAF3minigene assaymolecular diagnosisprimary ciliary dyskinesia (PCD)variants of uncertain significance (VUS)

Identifiers

PMID39764684
PMCPMC11705539

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