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Characteristic genetic spectrum of primary ciliary dyskinesia in Japanese patients and global ethnic heterogeneity: population-based genomic variation database analysis


Primary ciliary dyskinesia (PCD) is a hereditary disease caused by pathogenic variants in genes associated with motile cilia. Some variants responsible for PCD are reported to be ethnic-specific or geographical-specific. To identify the responsible PCD variants of Japanese PCD patients, we performed next-generation sequencing of a panel of 32 PCD genes or whole-exome sequencing in 26 newly identified Japanese PCD families. We then combined their genetic data with those from 40 Japanese PCD families reported previously, for an overall analysis of 66 unrelated Japanese PCD families. We conducted Genome Aggregation Database and TogoVar database analyses to reveal the PCD genetic spectrum of the Japanese population and compare with other ethnic groups worldwide. We identified 22 unreported variants among the 31 patients in the 26 newly identified PCD families, including 17 deleterious variants estimated to cause lack of transcription or nonsense-mediated mRNA decay and 5 missense mutations. In all 76 PCD patients from the 66 Japanese families, we identified 53 variants on 141 alleles in total. Copy number variation in DRC1 is the most frequent variant in Japanese PCD patients, followed by DNAH5 c.9018C>T. We found 30 variants specific to the Japanese population, of which 22 are novel. Furthermore, 11 responsible variants in the Japanese PCD patients are common in East Asian populations, while some variants are more frequent in other ethnic groups. In conclusion, PCD is genetically heterogeneous between different ethnicities, and Japanese PCD patients have a characteristic genetic spectrum.

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This research was funded by JSPS Grants-in-Aid for Scientific Research (C) (Grant Numbers 16K11210, 19K09886 and 22K09665), and (B) 22H03077 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, the Takeda Science Foundation, the Society for Promotion of International Oto-Rhino[1]Laryngology (SPIO) SODA TOYOJI SPIO Research Grant Program 2021, and AMED (Grant Number JP19ek0109410).

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KT and YX designed and conceptualized the study. YX, GF, TY, and SM performed analysis and interpreted the data. MN, MI, and MT performed the experiments. YX drafted the manuscript. SG and KT reviewed the manuscript. KT acquired the funding. KT acts as guarantor and accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. All authors critically revised the manuscript, contributed significantly to this work and declared to meet the ICMJE criteria for authorship.

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Correspondence to Kazuhiko Takeuchi.

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Xu, Y., Feng, G., Yano, T. et al. Characteristic genetic spectrum of primary ciliary dyskinesia in Japanese patients and global ethnic heterogeneity: population-based genomic variation database analysis. J Hum Genet 68, 455–461 (2023).

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