Primary ciliary dyskinesia caused by a large homozygous deletion including exons 1–4 of <i>DRC1</i> in Japanese patients with recurrent sinopulmonary infection

Keicho, Naoto; Hijikata, Makoto; Morimoto, Kozo; Homma, Sakae; Terada, Yoshio; Azuma, Arata; Kudoh, Shoji

doi:10.1002/mgg3.1033

Cited by 27 publications

(15 citation statements)

References 36 publications

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“…The mean Lund-Mackay score was 12.8 (range, 7-17) points, which is comparable to the score of 10.6 (range, [6][7][8][9][10][11][12][13][14][15][16] reported in a PCD cohort [26] and to those reported in children with cystic fibrosis (17.3 for patients undergoing surgery and 11.5 for those treated medically) [27] . It has been reported that the Lund-Mackay score is not a predictor for endoscopic sinus surgery or hospitalization in PCD patients [28] .…”

Section: Article In Pressmentioning

confidence: 53%

“…Disease-causing variants differ markedly among white European (52% of families carry DNAH5 or DNAH11 variants), Arab (42% of families carry CCDC39 or CCDC40 variants), and South Asian (36% of families carry single LRRC6 or CCDC103 variants) patients with PCD [9] . Recently, it has become apparent that DRC1 is the major cause of PCD in Japanese patients [10][11][12] . Differences in the causative genes might affect the clinical features in different ethnic groups.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of the clinical features of Japanese patients with primary ciliary dyskinesia

Chiyonobu

Feng

et al. 2022

Auris Nasus Larynx

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Primary ciliary dyskinesia (PCD) is a rare hereditary disease. Most reports of PCD in Japan are case reports, and clinical analysis has not been performed. Differences in the causative genes might affect the clinical features in different ethnic groups. The purpose of this study was to clarify the clinical features of Japanese patients with PCD. Methods: We performed a retrospective chart review of PCD patients seen at Mie University Hospital and patients whose blood samples were sent to us for genetic analysis from 2011 to 2020. Data on the following items were collected and analyzed: age at first visit to the hospital, age at diagnosis of PCD, process of referral to our facility, chief complaint, situs status, PrImary CiliARy DyskinesiA Rule (PICADAR) score, nasal nitric oxide concentration, otoscopic findings, rhinoscopic findings, and paranasal computed tomography scan findings. Results: Sixty-seven patients (24 male, 43 female) were diagnosed with PCD during the study period. Age at diagnosis ranged from 2 months to 69 years (median, 17 years). Respiratory symptoms (77%) were the most common complaint, followed by nasal (15%) and aural (8%) symptoms. Situs inversus was present in 17 (25%) cases. Only 2 cases had congenital cardiac anomalies. The mean PICADAR score was 7.3 (range, 3-14) points. Approximately 50% of tympanic membranes showed retraction, suggesting otitis media with effusion. The mean Lund-Mackay score was 12.8 (range, 7-17) points, suggesting that the radiographic findings were not always severe. There was no significant difference in the total Lund-Mackay score between patients with and without situs inversus (12.7 vs. 12.6, respectively). Conclusion: Situs inversus was present in 25% of Japanese PCD patients, which is much lower than observed in other countries. This is a result of differences in the major disease-causing

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Section: Article In Pressmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Analysis of the clinical features of Japanese patients with primary ciliary dyskinesia

Chiyonobu

Feng

et al. 2022

Auris Nasus Larynx

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“…Despite the added benefits of detecting deep intronic variants, intergenic variants, and CNV by GS, no functionally relevant CNV mutations were detected in this study. As CNV mutations were detected in PCD patients from other studies, the lack of detection could be attributed to the small sample size or differences in genetic etiology (Morimoto et al, 2019;Keicho et al, 2020;Wheway et al, 2021). This reduced the added benefits of GS in comparison to rES.…”

Section: Discussionmentioning

confidence: 97%

“…Multiple studies have identified CNV in PCD-related genes which contribute to a genetic diagnosis. Furthermore, a 27,748-bp large CNV deletion in DRC1 and a 3,549-bp large deletion in DNAAF4 were reported as founder mutations in East Asian and Irish populations, respectively ( Zariwala et al, 1993 ; Keicho et al, 2020 ). At this time, there is no consensus by the ERS and ATS guidelines on which genes should be evaluated for PCD, and current commercial panels are not inclusive of all genes associated with PCD ( Shoemark et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Functional Evaluation and Genetic Landscape of Children and Young Adults Referred for Assessment of Bronchiectasis

et al. 2022

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Bronchiectasis is the abnormal dilation of the airway which may be caused by various etiologies in children. Beyond the more recognized cause of bacterial and viral infections and primary immunodeficiencies, other genetic conditions such as cystic fibrosis and primary ciliary dyskinesia (PCD) can also contribute to the disease. Currently, there is still debate on whether genome sequencing (GS) or exome sequencing reanalysis (rES) would be beneficial if the initial targeted testing results returned negative. This study aims to provide a back-to-back comparison between rES and GS to explore the best integrated approach for the functional and genetics evaluation for patients referred for assessment of bronchiectasis. In phase 1, an initial 60 patients were analyzed by exome sequencing (ES) with one additional individual recruited later as an affected sibling for ES. Functional evaluation of the nasal nitric oxide test, transmission electron microscopy, and high-speed video microscopy were also conducted when possible. In phase 2, GS was performed on 30 selected cases with trio samples available. To provide a back-to-back comparison, two teams of genome analysts were alternatively allocated to GS or rES and were blinded to each other’s analysis. The time for bioinformatics, analysis, and diagnostic utility was recorded for evaluation. ES revealed five positive diagnoses (5/60, 8.3%) in phase 1, and four additional diagnoses were made by rES and GS (4/30, 13%) during phase 2. Subsequently, one additional positive diagnosis was identified in a sibling by ES and an overall diagnostic yield of 10/61 (16.4%) was reached. Among those patients with a clinical suspicion of PCD (n = 31/61), the diagnostic yield was 26% (n = 8/31). While GS did not increase the diagnostic yield, we showed that a variant of uncertain significance could only be detected by GS due to improved coverage over ES and hence is a potential benefit for GS in the future. We show that genetic testing is an essential component for the diagnosis of early-onset bronchiectasis and is most effective when used in combination with functional tools such as TEM or HSVM. Our comparison of rES vs. GS suggests that rES and GS are comparable in clinical diagnosis.

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“…Considering genes related to pulmonary diseases (PD), we identified two variants in the DRC1 gene significantly associated with COVID-19 severe outcome. Previous studies from Japan showed that variation (large homozygous deletion) in DRC1 plays an important role in primary ciliary dyskinesia (PCD), a rare genetic disorder that prevents the clearance of mucous from the lungs, leading to frequent respiratory infections caused by bacteria and other irritants in the mucous [ 20 , 21 , 22 ]. Moreover, the DRC1 / CCDC164 mutation significant in PCD was identified in India [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Gene Variants Related to Cardiovascular and Pulmonary Diseases May Correlate with Severe Outcome of COVID-19

Sypniewski

Król

Szyda

et al. 2022

IJMS

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Background: Severe outcomes of COVID-19 account for up to 15% of all cases. The study aims to check if any gene variants related to cardiovascular (CVD) and pulmonary diseases (PD) are correlated with a severe outcome of COVID-19 in a Polish cohort of COVID-19 patients. Methods: In this study, a subset of 747 samples from unrelated individuals collected across Poland in 2020 and 2021 was used and whole-genome sequencing was performed. Results: The GWAS analysis of SNPs and short indels located in genes related to CVD identified one variant significant in COVID-19 severe outcome in the HADHA gene, while for the PD gene panel, we found two significant variants in the DRC1 gene. In this study, both potentially protective and risk variants were identified, of which variants in the HADHA gene deserve the most attention. Conclusions: This is the first study reporting the association between the HADHA and DRC1 genetic variants and COVID-19 severe outcome based on the cohort WGS analysis. Although all the identified variants are localised in introns, they may be correlated and therefore inherited along with other risk variants, potentially causative to severe outcome of COVID-19 but not discovered yet.

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Primary ciliary dyskinesia caused by a large homozygous deletion including exons 1–4 of DRC1 in Japanese patients with recurrent sinopulmonary infection

Cited by 27 publications

References 36 publications

Analysis of the clinical features of Japanese patients with primary ciliary dyskinesia

Analysis of the clinical features of Japanese patients with primary ciliary dyskinesia

Functional Evaluation and Genetic Landscape of Children and Young Adults Referred for Assessment of Bronchiectasis

Gene Variants Related to Cardiovascular and Pulmonary Diseases May Correlate with Severe Outcome of COVID-19

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