Severe Bronchiectasis and Chronic Rhinosinusitis Due to Homozygous WFDC2 Variants: The First Three Cases Reported from Japan

Severe Bronchiectasis and Chronic Rhinosinusitis Due to Homozygous WFDC2 Variants: The First Three Cases Reported from Japan | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Severe Bronchiectasis and Chronic Rhinosinusitis Due to Homozygous WFDC2 Variants: The First Three Cases Reported from Japan Masashi Ito, Kozo Morimoto, Minako Hijikata, Hirotsugu Hasegawa, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5949796/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Apr, 2025 Read the published version in Respiratory Medicine Case Reports → Version 1 posted You are reading this latest preprint version Abstract We report the first three cases of bronchiectasis caused by homozygous WFDC2 variants in Japan. The ages at diagnosis of bronchiectasis were 18, 24, and 16 years, and all patients had a history of chronic sinusitis since childhood. Despite low nasal nitric oxide levels, the radiologic features resembled those of cystic fibrosis, characterized by bronchiectasis predominantly in the upper lobes. All patients experienced frequent exacerbations and respiratory dysfunction, even with long-term macrolide therapy. Consequently, two of the three patients required lung transplantation. Considering the possibility of founder mutations, WFDC2 variants should be included in diagnostic panels for patients with sinopulmonary disease in Asian populations. noncystic fibrosis bronchiectasis cystic fibrosis primary ciliary dyskinesia WFDC2 sinopulmonary disease Figures Figure 1 Introduction Refractory chronic airway disease that usually presents with bronchiectasis and chronic rhinosinusitis has historically caused significant clinical and diagnostic challenges due to diverse etiologies and overlapping clinical presentations 1 – 3 . Over the past decade, next-generation sequencing technology has significantly contributed to understanding several diseases, such as primary ciliary dyskinesia (PCD), primary immunodeficiency, and cystic fibrosis (CF) 4 – 7 . However, cases with undiagnosed conditions persist, and these cases often present low levels of nasal nitric oxide (nNO) and are preliminarily diagnosed as probable PCD in Japanese settings where CF is rare 8 . WAP four-disulfide core domain 2 ( WFDC2 ) variants have recently emerged as a novel cause of severe sinopulmonary disease. It is expressed predominantly in secretory cells of the respiratory epithelium and submucosal glands, and defects in its expression result in deficient antibacterial activity and antiprotease activity 9 . In the original study by Dougherty GW et al., WFDC2 mutations were shown to resemble CF rather than PCD, presenting nasal polyps and upper lobe predominant bronchiectasis 10 . A recent study from Korea highlighted a founder mutation of WFDC2 in the population, with findings similar to those of the original study 11 . Previously, we identified a founder mutation in dynein regulatory complex subunit 1 ( DRC1 ) as a possible cause of PCD in Japan and Korea 12 , prompting further investigation to identify the same WFDC2 mutation in cases that remained undiagnosed with PCD. This case series presents the first three novel cases of WFDC2 -associated severe sinopulmonary disease in Japan. Through detailed clinical and genetic analyses, we aimed to elucidate the phenotypic spectrum of WFDC2 variants in Japanese patients, contributing to improved awareness and management of this condition. Case Series Case 1 (FRC-48) A 31-year-old woman was referred to the outpatient clinic for evaluation of PCD. The patient had undergone surgical treatment for sinusitis at the age of 9 and had been diagnosed with sinopulmonary disease at the age of 18 on the basis of her clinical history of sinusitis and bronchiectasis. She stopped visiting the previous hospital at the age of 27 but restarted long-term macrolide therapy at the age of 31 after being treated for pneumonia. No family history was reported except for sinusitis in her grandmother. The pulmonary function test revealed a mixed impairment pattern (VC 1.68 L, percent predicted VC 57.3%, FEV 1 1.15 L, percent predicted FEV 1 66.5%). A chest computed tomography (CT) scan revealed diffuse bronchiectasis predominantly in the upper lobes (Fig. 1 A). The sinus CT scan demonstrated hypoplasia in the maxillary sinus (Fig. 1 B). Mucoid Pseudomonas aeruginosa was repeatedly isolated from sputum cultures. For the PCD diagnostic test, the nNO level was low at 15.5 nL/min, but electron microscopy revealed a normal ciliary ultrastructure, and no pathogenic variants were identified in our PCD-causative gene panel 13 . Additionally, no cystic fibrosis transmembrane conductance regulator ( CFTR ) mutations were detected. Coding exons (exons 1–3 of NM_006103.4) of WFDC2 were amplified by PCR from genomic DNA, and Sanger sequencing of the PCR products revealed a homozygous missense variant, NM_006103.4:c.291C > G (p.Cys97Trp) (Fig. 1 C). For treatment, patients routinely practice airway clearance techniques (ACT), including the active cycle of breathing technique (ACBT) and oscillating positive expiratory pressure (OPEP), along with long-term macrolide therapy. She was referred to a specialized center for lung transplantation. Case 2 (FRC-104) A 42-year-old woman was referred to our hospital for the treatment of severe bronchiectasis. The patient had been diagnosed with bronchiectasis when she was 24 years old. Since then, she has undergone long-term macrolide therapy. She has also received multiple courses of oral and intravenous antibiotics to treat bronchiectasis exacerbations. Additionally, she had undergone surgical treatment for chronic sinusitis three times. She reported a family history of respiratory disease in her grandfather, but specific details were not available. On admission, P. aeruginosa was isolated from her sputum culture. Pulmonary function tests revealed obstructive impairment (VC 2.66 L, percent predicted VC 82.6%; FEV 1 1.28 L, percent predicted FEV 1 52.0%). Chest CT scans revealed diffuse bronchiectasis predominantly in the right upper lobe (Fig. 1 A). Sinus CT revealed hypoplasia in the maxillary sinus. Additionally, the frontal sinus was aplastic (Fig. 1 B). For the PCD diagnostic test, the nNO level was low at 10.2 nL/min, but electron microscopy revealed a normal ciliary ultrastructure. No pathogenic variants were identified in PCD-associated genes or in CFTR gene. PCR and Sanger sequencing of the genomic DNA revealed the same homozygous missense variant of WFDC2 (p.Cys97Trp) (Fig. 1 C). For the treatment plan, we prioritized intensive ACT and rehabilitation and proposed lung transplantation as a definitive intervention. Additionally, voriconazole was prescribed to treat chronic Aspergillus pulmonary disease. During her admission, no exacerbations occurred, and she successfully underwent lung transplantation at a specialized center three months after admission. Case 3 (FRC-191) A 34-year-old woman was referred to the outpatient clinic for evaluation of PCD. The patient underwent surgery for chronic sinusitis at the age of 10. At the age of 16, she was hospitalized due to hemoptysis and was subsequently diagnosed with bronchiectasis. Since then, she has been receiving long-term macrolide therapy. Her older brother was also diagnosed with bronchiectasis. Pulmonary function tests revealed a mixed impairment pattern (VC 1.95 L, percent predicted VC 55.9%, FEV 1 1.90 L, percent predicted FEV 1 39.4%). Her chest CT scans revealed diffuse bronchiectasis, predominantly in the upper lobes (Fig. 1 A). Sinus CT scans revealed aplasia of the frontal sinus (Fig. 2B). Mucoid P. aeruginosa and methicillin-sensitive Staphylococcus aureus were cultured from her sputum samples. For the PCD diagnostic test, the nNO level was low at 48.9 nL/min. Electron microscopy revealed a normal ciliary ultrastructure. There were no pathogenic variants in PCD-associated genes or CFTR gene. PCR and Sanger sequencing of the genomic DNA revealed the same homozygous missense variant of WFDC2 (p.Cys97Trp) (Fig. 1 C). For treatment, she continued long-term macrolide therapy. We introduced ACT and recommended routine vaccinations. Discussion In the present study, as hypothesized, WFDC2 variants (c.291C > G; p.Cys97Trp; homozygous) were identified in our cohort, suggesting that this variant may be the founder mutation in Japanese patients, as it is in Korean patients. All patients had similar clinical phenotypes, including diffuse bronchiectasis, chronic rhinosinusitis, chronic P. aeruginosa infection, and low nNO levels. However, the radiological presentations were more indicative of CF, as characterized by upper lobe predominant bronchiectasis and severe respiratory dysfunction in young individuals. These findings align with previously reported cases. Importantly, while long-term macrolide therapy was introduced, all patients underwent multiple courses of antibiotic treatment and developed respiratory failure, with two patients requiring lung transplantation. These findings underscore the importance of early diagnosis using genetic testing for bronchiectasis caused by WFDC2 variants, as well as for PCD and CF, and emphasize the need for appropriate management at tertiary care hospitals. Together with the previously reported case series, the male-to-female ratio was approximately 50:50, and the median age at testing for WFDC2 deficiency was 31 (interquartile range [IQR] 22–46) years (Table 1). The median nNO level was extremely low at 13.8 (IQR 9.0–17.1) nL/min. Although none of our three patients had a history of NRD, three patients in a previous report from the United States experienced unexplained NRD. In addition, WFDC2 variants are potentially associated with female infertility. In contrast, no cases of male infertility have been reported. To clarify the association between WFDC2 variants and infertility, further studies with a larger number of patients, as well as detailed urological and gynecological evaluations, are needed. WFDC2 is a protein known to possess antimicrobial activity 14 . In individuals with missense variants in cysteine residues within the WAP domain, which is essential for the functional WFDC domain, the secretion of WFDC2 in saliva, seminal fluid, and airway surface liquid is significantly reduced, accompanied by decreased serum concentrations of WFDC2 10 . These findings suggest that assessing WFDC2 expression through saliva and blood tests could serve as a valuable tool for screening and differential diagnosis. Thus, early diagnosis of WFDC2 -related bronchiectasis may become feasible. Furthermore, timely intervention with protein replacement therapy could improve patient outcomes. In 2016, we started a PCD clinic, and approximately 230 patients underwent diagnostic tests. Among the 31 patients with low nNO levels (< 77 nL/min) but no PCD or CF gene mutations, three (9.7%) were identified homozygous missense variant of WFDC2 . According to the short-read whole-genome sequencing-based variant database of approximately 60,000 Japanese individuals (ToMMo 60KJPN), the allele frequency of the WFDC2 variant (c.291C > G; p.Cys97Trp, chr20:45,480,009 C > G, rs780739822) is 0.000734 15 ( https://jmorp.megabank.tohoku.ac.jp/ ). This suggests that WFDC2 variants should be included in the diagnostic workup for patients with chronic sinopulmonary disease, alongside PCD panels, particularly in Japanese and Korean populations. Because WFDC2 variants are associated with a more severe clinical course, patients with WFDC2 variants require strong support from medical and social systems. We identified three cases with WFDC2 variants. Therefore, further research involving other Japanese cohorts is warranted to generalize and conduct more detailed findings and geographical analysis. Because WFDC2 variants cause severe bronchiectasis in young individuals, the development of specific drugs targeting this variant is encouraged, in addition to ongoing efforts to treat PCD. Declarations Conflict of interest statement: The authors state that they have no conflicts of interest. Author contribution statement: M.I. and K.M. collected the clinical data and wrote the manuscript. M.H. and N.K. designed the study, analyzed the data, and revised the manuscript. H.H. provided the clinical data. K.W. and A.M. analyzed the data. All the authors critically read and commented on the manuscript. Ethics Statement: The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images, and this study was approved by the institutional review board of Fukujuji Hospital (#24018). Funding statement: This research was funded by the Health, Labor, and Welfare Science Research Grants-in-Aid for Intractable Diseases under “Research on diffuse lung diseases”, as well as JSPS KAKENHI (Grant Numbers JP22K08297 and JP23K07616). References Araújo D, Shteinberg M, Aliberti S, Goeminne PC, Hill AT, Fardon T, Obradovic D, Dimakou K, Polverino E, De Soyza A, McDonnell MJ, Chalmers JD (2017) Standardised classification of the aetiology of bronchiectasis using an objective algorithm. Eur Respir J. ; 50 Yu I, Yong SJ, Lee WY, Kim SH, Lee H, Na JO, Kim DK, Oh YM, Lee JH (2022) Prevalence of chronic rhinosinusitis and its relating factors in patients with bronchiectasis: findings from KMBARC registry. 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Nat Rev Dis Primers 6:77 Shoemark A, Griffin H, Wheway G, Hogg C, Lucas JS, Camps C, Taylor J, Carroll M, Loebinger MR, Chalmers JD, Morris-Rosendahl D, Mitchison HM, De Soyza A, Brown D, Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred CR, Brittain H, Caulfield MJ, Chan GC, Fowler T, Giess A, Hamblin A, Henderson S, Hubbard TJP, Jackson R, Jones LJ, Kasperaviciute D, Kayikci M, Kousathanas A, Lahnstein L, Leigh SEA, Leong IUS, Lopez FJ, Maleady-Crowe F, McEntagart M, Minneci F, Moutsianas L, Mueller M, Murugaesu N, Need AC, O'Donovan P, Odhams CA, Patch C, Perez-Gil D, Pereira MB, Pullinger J, Rahim T, Rendon A, Rogers T, Savage K, Sawant K, Scott RH, Siddiq A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M, Taylor Tavares AL, Thomas ERA, Thompson SR, Tucci A, Welland MJ, Williams E, Witkowska K, Wood SM (2022) Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis. Eur Respir J. ; 60 Sun J, Yang L, Lu Y, Wang H, Peng X, Dong X, Cheng G, Cao Y, Wu B, Wang X, Zhou W (2020) Screening for primary immunodeficiency diseases by next-generation sequencing in early life. Clin Transl Immunol 9:e1138 Guan WJ, Li JC, Liu F, Zhou J, Liu YP, Ling C, Gao YH, Li HM, Yuan JJ, Huang Y, Chen CL, Chen RC, Zhang X, Zhong NS (2018) Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis 10:2618–2630 Shapiro AJ, Davis SD, Leigh MW, Knowles MR, Lavergne V, Ferkol T (2020) Limitations of Nasal Nitric Oxide Testing in Primary Ciliary Dyskinesia. Am J Respir Crit Care Med 202:476–477 Nakajima K, Ono M, Radović U, Dizdarević S, Tomizawa SI, Kuroha K, Nagamatsu G, Hoshi I, Matsunaga R, Shirakawa T, Kurosawa T, Miyazaki Y, Seki M, Suzuki Y, Koseki H, Nakamura M, Suda T, Ohbo K (2019) Lack of whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (WFDC2) causes neonatal death from respiratory failure in mice. Dis Model Mech. ; 12 Dougherty GW, Ostrowski LE, Nöthe-Menchen T, Raidt J, Schramm A, Olbrich H, Yin W, Sears PR, Dang H, Smith AJ, Beule AG, Hjeij R, Rutjes N, Haarman EG, Maas SM, Ferkol TW, Noone PG, Olivier KN, Bracht DC, Barbry P, Zaragosi LE, Fierville M, Kliesch S, Wohlgemuth K, König J, George S, Loges NT, Ceppe A, Markovetz MR, Luo H, Guo T, Rizk H, Eldesoky T, Dahlke K, Boldt K, Ueffing M, Hill DB, Pang YP, Knowles MR, Zariwala MA, Omran H (2024) Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis. Am J Respir Crit Care Med 210:63–76 Roh JW, Oh J, Kim SJ, Hong JW, Ohk J, Shim HS, Cho H-J, Woo A, Kim SY, Jung H (2024) The founder missense mutation of WFDC2 leads to severe respiratory distress accompanied by bronchiectasis and rhinosinusitis. medRxiv. : 2024.11. 16.24317083. Morimoto K, Hijikata M, Zariwala MA, Nykamp K, Inaba A, Guo TC, Yamada H, Truty R, Sasaki Y, Ohta K, Kudoh S, Leigh MW, Knowles MR, Keicho N (2019) Recurring large deletion in DRC1 (CCDC164) identified as causing primary ciliary dyskinesia in two Asian patients. Mol Genet Genomic Med 7:e838 Hijikata M, Morimoto K, Ito M, Wakabayashi K, Miyabayashi A, Yamada H, Keicho N (2025) Genetic Variants Supporting the Diagnosis of Primary Ciliary Dyskinesia in Japan. Clin Genet 107:219–223 Watt AP, Sharp JA, Lefevre C, Nicholas KR (2012) WFDC2 is differentially expressed in the mammary gland of the tammar wallaby and provides immune protection to the mammary gland and the developing pouch young. Dev Comp Immunol 36:584–590 Kuriyama S, Yaegashi N, Nagami F, Arai T, Kawaguchi Y, Osumi N, Sakaida M, Suzuki Y, Nakayama K, Hashizume H, Tamiya G, Kawame H, Suzuki K, Hozawa A, Nakaya N, Kikuya M, Metoki H, Tsuji I, Fuse N, Kiyomoto H, Sugawara J, Tsuboi A, Egawa S, Ito K, Chida K, Ishii T, Tomita H, Taki Y, Minegishi N, Ishii N, Yasuda J, Igarashi K, Shimizu R, Nagasaki M, Koshiba S, Kinoshita K, Ogishima S, Takai-Igarashi T, Tominaga T, Tanabe O, Ohuchi N, Shimosegawa T, Kure S, Tanaka H, Ito S, Hitomi J, Tanno K, Nakamura M, Ogasawara K, Kobayashi S, Sakata K, Satoh M, Shimizu A, Sasaki M, Endo R, Sobue K (2016) Tohoku Medical Megabank Project Study Group T, Yamamoto M. The Tohoku Medical Megabank Project: Design and Mission. J Epidemiol 26:493–511 Tables Table 1 Literature review on clinical findings in patients with WFDC2 variants, including the present cases. FRC-48, FRC-104, and FRC-191 were cases from Fukujuji Hospital in Japan. UNC-376 II1, OP-2147 II1, OP-2032 II1, OP-1837 II1, OP-4281 II1, UNC-231 II1, OP-398 II1, UNC-186 II1, UNC-186 II2, CSU-150 II2, and OP-4474 II1 were reported from the United States 10 . P1946-21, P1969-21, P2678-21, P2783-21, P5-21, and P5-22 were reported from Korea 11 . WFDC2 vatriants Age at testing for WFDC2 variants Sex Bronchiectasis Neonatal respiratory distress Sinusitis Otitis media Nasal nitric oxide (nL/min) Percent predicted FEV 1 (%) P. aeruginosa Infertility Lung transplant Number of cases (%) or median [IQR] 31 [22, 46]* Female 11/20 (55) 17/18 (94.4) 3/6 (50) 20/20 (100) 9/14 (64.3) 13.8 [9.0, 17.1] 52 [29, 67] 15/15 (100) Total 3/5 (60), Male 0/2 (0), Female 3/3 (100) 5/20 (25) FRC-48 (Case 1) c.291C>G; p.Cys97Trp; hom. 31 F Yes No Yes Yes 15.5 66.5 Yes N/A No FRC-104 (Case 2) c.291C>G; p.Cys97Trp; hom. 42 F Yes No Yes Yes 10.2 52.0 Yes N/A Yes FRC-191 (Case 3) c.291C>G; p.Cys97Trp; hom. 34 F Yes No Yes No 48.9 39.4 Yes N/A No UNC-376 II1 c.2T>A; p.Met1? het. deletion, het. 22 F Yes N/A Yes Yes 16.8 73 Yes N/A No OP-2147 II1 c.145T>C; p.Cys49Arg; hom. 30 M Yes Yes Yes Yes 5.5 79 Yes No No OP-2032 II1 c.145T>C; p.Cys49Arg; het. deletion exon 1-2; het. 14 M Yes N/A Yes Yes 5.3 67 Yes N/A No OP-1837 II1 c.145T>C; p.Cys49Arg; hom. 52 M Yes N/A Yes No 16.6 N/A Yes N/A No OP-4281 II1 c.145T>C; p.Cys49Arg; hom. 19 M Yes N/A Yes No 2.3 38 Yes N/A No UNC-231 II1 c.145T>C; p.Cys49Arg; hom. 52 F Yes Yes Yes No 33.7 41.6 Yes Yes No OP-398 II1 c.145T>C; p.Cys49Arg; het. c.271G>A; p.Gly91Ser; het. 26 F N/A N/A Yes Yes N/A N/A N/A N/A No UNC-186 II1 c.145T>C; p.Cys49Arg; het. c.307T>C; p.Cys103Arg; het. 46 M Yes Yes Yes Yes 10.8 64 Yes No No UNC-186 II2 c.145T>C; p.Cys49Arg; het. c.307T.C; p.Cys103Arg; het. 51 F Yes N/A Yes Yes 17.8 25 Yes Yes Yes CSU-150 II2 c.307T>C; p.Cys103Arg; hom. 48 F Yes N/A Yes No 12 22 Yes Yes No OP-4474 II1 c.326G>A; p.Cys109Tyr; hom. 7 M No N/A Yes Yes N/A 67 N/A N/A No P1946-21 c.291C>G; p.Cys97Trp; hom. 31–35 M N/A N/A Yes N/A N/A N/A N/A N/A No P1969-21 c.291C>G; p.Cys97Trp; hom. 36–40 F Yes N/A Yes N/A N/A 29 Yes N/A Yes P2678-21 c.291C>G; p.Cys97Trp; hom. 46–50 F Yes N/A Yes N/A N/A 21 Yes N/A Yes P2783-21 c.291C>G; p.Cys97Trp; hom. 31–35 F Yes N/A Yes N/A N/A 22 Yes N/A Yes P5-21 c.291C>G; p.Cys97Trp; hom. 21–25 M Yes N/A Yes N/A N/A 85 N/A N/A No P5-22 c.291C>G; p.Cys97Trp; hom. 21–25 M Yes N/A Yes N/A N/A 71 N/A N/A No hom=homozygous; het=heterozygous; F=female; M=male; N/A=data not available *We calculated it under the assumption that P1946-21 was 31 years old, P1969-21 was 36 years old, P2678-21 was 46 years old, P2783-21 was 31 years old, P5-21 was 21 years old, and P5-22 was 21 years old. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Published Journal Publication published 21 Apr, 2025 Read the published version in Respiratory Medicine Case Reports → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5949796","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":410434052,"identity":"acc6dd06-9802-4c61-9731-1dec5b58c757","order_by":0,"name":"Masashi Ito","email":"","orcid":"https://orcid.org/0000-0002-9498-6995","institution":"Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.","correspondingAuthor":false,"prefix":"","firstName":"Masashi","middleName":"","lastName":"Ito","suffix":""},{"id":410434053,"identity":"47b30de0-5dd9-42e3-b317-205391e6b706","order_by":1,"name":"Kozo Morimoto","email":"","orcid":"https://orcid.org/0000-0002-8239-9275","institution":"Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.","correspondingAuthor":false,"prefix":"","firstName":"Kozo","middleName":"","lastName":"Morimoto","suffix":""},{"id":410434054,"identity":"f453ac1f-0645-4da9-9f0b-76b9f59f6a5a","order_by":2,"name":"Minako Hijikata","email":"","orcid":"","institution":"Department of Pathophysiology and Host Defense, the Research Institute of Tuberculosis, Japan Anti‐Tuberculosis Association, Tokyo, Japan","correspondingAuthor":false,"prefix":"","firstName":"Minako","middleName":"","lastName":"Hijikata","suffix":""},{"id":410434055,"identity":"f262b0a2-25d6-4676-86a9-f20122f28ec6","order_by":3,"name":"Hirotsugu Hasegawa","email":"","orcid":"","institution":"Department of Respiratory Medicine, Respiratory Disease Center, Seirei Mikatahara General Hospital, Hamamatsu, Japan.","correspondingAuthor":false,"prefix":"","firstName":"Hirotsugu","middleName":"","lastName":"Hasegawa","suffix":""},{"id":410434056,"identity":"acb2c882-f2cb-48da-9489-d3b57d1d46f2","order_by":4,"name":"Keiko Wakabayashi","email":"","orcid":"","institution":"Department of Pathophysiology and Host Defense, the Research Institute of Tuberculosis, Japan Anti‐Tuberculosis Association, Tokyo, Japan","correspondingAuthor":false,"prefix":"","firstName":"Keiko","middleName":"","lastName":"Wakabayashi","suffix":""},{"id":410434057,"identity":"77b06b3c-7a98-4c85-9d60-4a9d460d73b1","order_by":5,"name":"Akiko Miyabayashi","email":"","orcid":"","institution":"Department of Pathophysiology and Host Defense, the Research Institute of Tuberculosis, Japan Anti‐Tuberculosis Association, Tokyo, Japan","correspondingAuthor":false,"prefix":"","firstName":"Akiko","middleName":"","lastName":"Miyabayashi","suffix":""},{"id":410434058,"identity":"eff843d8-18db-4fef-a2c7-a35241c6d7ae","order_by":6,"name":"Naoto Keicho","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYDACHgaGA4wNDHJADAFwBiEtxowNzCRoAalKbGBgJtJd5jyHDx74ucMmvbn9/MEPDBX3GJhnE7DGsrct4WDvmbTcxp5kZgmGM8UMjHMO4NdicJ7H4DBj2+HcxoZkBgnGtgQGxhkJhLTwfwBpSWfsf8z8gzgtZ3sYQFoSGGcksxFpy5ljBgd729IMG2c8NrNIOJPAQ9gvZ5Iff/jZZiNv2J/4+MaHigQ5Q0IhBgeGIIVAJ/EYziBSB4M8nCFBrJZRMApGwSgYKQAAnatH0LLWG3MAAAAASUVORK5CYII=","orcid":"","institution":"The Research Institute of Tuberculosis, Japan Anti‐Tuberculosis Association, Tokyo, Japan","correspondingAuthor":true,"prefix":"","firstName":"Naoto","middleName":"","lastName":"Keicho","suffix":""}],"badges":[],"createdAt":"2025-02-03 09:19:36","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":true,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-5949796/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5949796/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1016/j.rmcr.2025.102214","type":"published","date":"2025-04-22T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":75519748,"identity":"ab5fa2c9-b90a-4407-a83a-4dba944513df","added_by":"auto","created_at":"2025-02-05 11:54:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1768550,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Chest computed tomography revealed diffuse bronchiectasis, predominantly in the upper lobe.\u003c/p\u003e\n\u003cp\u003e(B) Sinus computed tomography.\u003c/p\u003e\n\u003cp\u003e(C) Electropherograms of Sanger sequencing of \u003cem\u003eWFDC2\u003c/em\u003e gene.\u003c/p\u003e\n\u003cp\u003eGenomic DNA was amplified by PCR with the primers 5′-GATCTTCCTGGGCCTCCTGAGAGC-3′ and 5′-CTAACCTCCCTTCACCTCCGCCTG-3′. The PCR products weresubjected to Sanger sequencing via theprimer 5′-CCGCCTGGGTGACGTTTTCTCCTG-3′. The homozygous/hemizygous missense variant NM_006103.4:c.291C\u0026gt;G (p. Cys97Trp) was observed in all three cases. The blacktriangle indicates the position of the variant. The nucleotide sequence and deduced amino acid sequence are shown at the bottom.\u003c/p\u003e","description":"","filename":"Figure10203.png","url":"https://assets-eu.researchsquare.com/files/rs-5949796/v1/7300d0e56e91c6b0639b05f8.png"},{"id":83564322,"identity":"540f1c86-8d3b-4868-adb1-d337b27cfd7a","added_by":"auto","created_at":"2025-05-28 14:28:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2754952,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5949796/v1/60e1503b-4f0a-448e-be40-9d28f4ce255c.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eSevere Bronchiectasis and Chronic Rhinosinusitis Due to Homozygous \u003cem\u003eWFDC2 \u003c/em\u003eVariants: The First Three Cases Reported from Japan\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRefractory chronic airway disease that usually presents with bronchiectasis and chronic rhinosinusitis has historically caused significant clinical and diagnostic challenges due to diverse etiologies and overlapping clinical presentations \u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Over the past decade, next-generation sequencing technology has significantly contributed to understanding several diseases, such as primary ciliary dyskinesia (PCD), primary immunodeficiency, and cystic fibrosis (CF) \u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. However, cases with undiagnosed conditions persist, and these cases often present low levels of nasal nitric oxide (nNO) and are preliminarily diagnosed as probable PCD in Japanese settings where CF is rare \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWAP four-disulfide core domain 2 (\u003cem\u003eWFDC2\u003c/em\u003e) variants have recently emerged as a novel cause of severe sinopulmonary disease. It is expressed predominantly in secretory cells of the respiratory epithelium and submucosal glands, and defects in its expression result in deficient antibacterial activity and antiprotease activity \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. In the original study by Dougherty GW et al., \u003cem\u003eWFDC2\u003c/em\u003e mutations were shown to resemble CF rather than PCD, presenting nasal polyps and upper lobe predominant bronchiectasis \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA recent study from Korea highlighted a founder mutation of \u003cem\u003eWFDC2\u003c/em\u003e in the population, with findings similar to those of the original study \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Previously, we identified a founder mutation in dynein regulatory complex subunit 1 (\u003cem\u003eDRC1\u003c/em\u003e) as a possible cause of PCD in Japan and Korea \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, prompting further investigation to identify the same \u003cem\u003eWFDC2\u003c/em\u003e mutation in cases that remained undiagnosed with PCD.\u003c/p\u003e \u003cp\u003eThis case series presents the first three novel cases of \u003cem\u003eWFDC2\u003c/em\u003e-associated severe sinopulmonary disease in Japan. Through detailed clinical and genetic analyses, we aimed to elucidate the phenotypic spectrum of \u003cem\u003eWFDC2\u003c/em\u003e variants in Japanese patients, contributing to improved awareness and management of this condition.\u003c/p\u003e"},{"header":"Case Series","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCase 1 (FRC-48)\u003c/h2\u003e \u003cp\u003eA 31-year-old woman was referred to the outpatient clinic for evaluation of PCD. The patient had undergone surgical treatment for sinusitis at the age of 9 and had been diagnosed with sinopulmonary disease at the age of 18 on the basis of her clinical history of sinusitis and bronchiectasis. She stopped visiting the previous hospital at the age of 27 but restarted long-term macrolide therapy at the age of 31 after being treated for pneumonia. No family history was reported except for sinusitis in her grandmother.\u003c/p\u003e \u003cp\u003eThe pulmonary function test revealed a mixed impairment pattern (VC 1.68 L, percent predicted VC 57.3%, FEV\u003csub\u003e1\u003c/sub\u003e 1.15 L, percent predicted FEV\u003csub\u003e1\u003c/sub\u003e 66.5%). A chest computed tomography (CT) scan revealed diffuse bronchiectasis predominantly in the upper lobes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The sinus CT scan demonstrated hypoplasia in the maxillary sinus (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Mucoid \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e was repeatedly isolated from sputum cultures.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFor the PCD diagnostic test, the nNO level was low at 15.5 nL/min, but electron microscopy revealed a normal ciliary ultrastructure, and no pathogenic variants were identified in our PCD-causative gene panel \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Additionally, no cystic fibrosis transmembrane conductance regulator (\u003cem\u003eCFTR\u003c/em\u003e) mutations were detected. Coding exons (exons 1\u0026ndash;3 of NM_006103.4) of \u003cem\u003eWFDC2\u003c/em\u003e were amplified by PCR from genomic DNA, and Sanger sequencing of the PCR products revealed a homozygous missense variant, NM_006103.4:c.291C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Cys97Trp) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eFor treatment, patients routinely practice airway clearance techniques (ACT), including the active cycle of breathing technique (ACBT) and oscillating positive expiratory pressure (OPEP), along with long-term macrolide therapy. She was referred to a specialized center for lung transplantation.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCase 2 (FRC-104)\u003c/h3\u003e\n\u003cp\u003eA 42-year-old woman was referred to our hospital for the treatment of severe bronchiectasis. The patient had been diagnosed with bronchiectasis when she was 24 years old. Since then, she has undergone long-term macrolide therapy. She has also received multiple courses of oral and intravenous antibiotics to treat bronchiectasis exacerbations. Additionally, she had undergone surgical treatment for chronic sinusitis three times. She reported a family history of respiratory disease in her grandfather, but specific details were not available.\u003c/p\u003e \u003cp\u003eOn admission, \u003cem\u003eP. aeruginosa\u003c/em\u003e was isolated from her sputum culture. Pulmonary function tests revealed obstructive impairment (VC 2.66 L, percent predicted VC 82.6%; FEV\u003csub\u003e1\u003c/sub\u003e 1.28 L, percent predicted FEV\u003csub\u003e1\u003c/sub\u003e 52.0%). Chest CT scans revealed diffuse bronchiectasis predominantly in the right upper lobe (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Sinus CT revealed hypoplasia in the maxillary sinus. Additionally, the frontal sinus was aplastic (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003eFor the PCD diagnostic test, the nNO level was low at 10.2 nL/min, but electron microscopy revealed a normal ciliary ultrastructure. No pathogenic variants were identified in PCD-associated genes or in \u003cem\u003eCFTR\u003c/em\u003e gene. PCR and Sanger sequencing of the genomic DNA revealed the same homozygous missense variant of \u003cem\u003eWFDC2\u003c/em\u003e (p.Cys97Trp) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eFor the treatment plan, we prioritized intensive ACT and rehabilitation and proposed lung transplantation as a definitive intervention. Additionally, voriconazole was prescribed to treat chronic \u003cem\u003eAspergillus\u003c/em\u003e pulmonary disease. During her admission, no exacerbations occurred, and she successfully underwent lung transplantation at a specialized center three months after admission.\u003c/p\u003e\n\u003ch3\u003eCase 3 (FRC-191)\u003c/h3\u003e\n\u003cp\u003eA 34-year-old woman was referred to the outpatient clinic for evaluation of PCD. The patient underwent surgery for chronic sinusitis at the age of 10. At the age of 16, she was hospitalized due to hemoptysis and was subsequently diagnosed with bronchiectasis. Since then, she has been receiving long-term macrolide therapy. Her older brother was also diagnosed with bronchiectasis.\u003c/p\u003e \u003cp\u003ePulmonary function tests revealed a mixed impairment pattern (VC 1.95 L, percent predicted VC 55.9%, FEV\u003csub\u003e1\u003c/sub\u003e 1.90 L, percent predicted FEV\u003csub\u003e1\u003c/sub\u003e 39.4%). Her chest CT scans revealed diffuse bronchiectasis, predominantly in the upper lobes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Sinus CT scans revealed aplasia of the frontal sinus (Fig.\u0026nbsp;2B). Mucoid \u003cem\u003eP. aeruginosa\u003c/em\u003e and methicillin-sensitive \u003cem\u003eStaphylococcus aureus\u003c/em\u003e were cultured from her sputum samples.\u003c/p\u003e \u003cp\u003eFor the PCD diagnostic test, the nNO level was low at 48.9 nL/min. Electron microscopy revealed a normal ciliary ultrastructure. There were no pathogenic variants in PCD-associated genes or \u003cem\u003eCFTR\u003c/em\u003e gene. PCR and Sanger sequencing of the genomic DNA revealed the same homozygous missense variant of \u003cem\u003eWFDC2\u003c/em\u003e (p.Cys97Trp) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003eFor treatment, she continued long-term macrolide therapy. We introduced ACT and recommended routine vaccinations.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study, as hypothesized, \u003cem\u003eWFDC2\u003c/em\u003e variants (c.291C\u0026thinsp;\u0026gt;\u0026thinsp;G; p.Cys97Trp; homozygous) were identified in our cohort, suggesting that this variant may be the founder mutation in Japanese patients, as it is in Korean patients. All patients had similar clinical phenotypes, including diffuse bronchiectasis, chronic rhinosinusitis, chronic \u003cem\u003eP. aeruginosa\u003c/em\u003e infection, and low nNO levels. However, the radiological presentations were more indicative of CF, as characterized by upper lobe predominant bronchiectasis and severe respiratory dysfunction in young individuals. These findings align with previously reported cases. Importantly, while long-term macrolide therapy was introduced, all patients underwent multiple courses of antibiotic treatment and developed respiratory failure, with two patients requiring lung transplantation. These findings underscore the importance of early diagnosis using genetic testing for bronchiectasis caused by \u003cem\u003eWFDC2\u003c/em\u003e variants, as well as for PCD and CF, and emphasize the need for appropriate management at tertiary care hospitals.\u003c/p\u003e \u003cp\u003eTogether with the previously reported case series, the male-to-female ratio was approximately 50:50, and the median age at testing for \u003cem\u003eWFDC2\u003c/em\u003e deficiency was 31 (interquartile range [IQR] 22\u0026ndash;46) years (Table\u0026nbsp;1). The median nNO level was extremely low at 13.8 (IQR 9.0\u0026ndash;17.1) nL/min. Although none of our three patients had a history of NRD, three patients in a previous report from the United States experienced unexplained NRD. In addition, \u003cem\u003eWFDC2\u003c/em\u003e variants are potentially associated with female infertility. In contrast, no cases of male infertility have been reported. To clarify the association between \u003cem\u003eWFDC2\u003c/em\u003e variants and infertility, further studies with a larger number of patients, as well as detailed urological and gynecological evaluations, are needed.\u003c/p\u003e \u003cp\u003eWFDC2 is a protein known to possess antimicrobial activity \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In individuals with missense variants in cysteine residues within the WAP domain, which is essential for the functional WFDC domain, the secretion of WFDC2 in saliva, seminal fluid, and airway surface liquid is significantly reduced, accompanied by decreased serum concentrations of WFDC2 \u003csup\u003e10\u003c/sup\u003e. These findings suggest that assessing \u003cem\u003eWFDC2\u003c/em\u003e expression through saliva and blood tests could serve as a valuable tool for screening and differential diagnosis. Thus, early diagnosis of \u003cem\u003eWFDC2\u003c/em\u003e-related bronchiectasis may become feasible. Furthermore, timely intervention with protein replacement therapy could improve patient outcomes.\u003c/p\u003e \u003cp\u003eIn 2016, we started a PCD clinic, and approximately 230 patients underwent diagnostic tests. Among the 31 patients with low nNO levels (\u0026lt;\u0026thinsp;77 nL/min) but no PCD or CF gene mutations, three (9.7%) were identified homozygous missense variant of \u003cem\u003eWFDC2\u003c/em\u003e. According to the short-read whole-genome sequencing-based variant database of approximately 60,000 Japanese individuals (ToMMo 60KJPN), the allele frequency of the \u003cem\u003eWFDC2\u003c/em\u003e variant (c.291C\u0026thinsp;\u0026gt;\u0026thinsp;G; p.Cys97Trp, chr20:45,480,009 C\u0026thinsp;\u0026gt;\u0026thinsp;G, rs780739822) is 0.000734 \u003csup\u003e15\u003c/sup\u003e (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://jmorp.megabank.tohoku.ac.jp/\u003c/span\u003e\u003cspan address=\"https://jmorp.megabank.tohoku.ac.jp/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). This suggests that \u003cem\u003eWFDC2\u003c/em\u003e variants should be included in the diagnostic workup for patients with chronic sinopulmonary disease, alongside PCD panels, particularly in Japanese and Korean populations. Because \u003cem\u003eWFDC2\u003c/em\u003e variants are associated with a more severe clinical course, patients with \u003cem\u003eWFDC2\u003c/em\u003e variants require strong support from medical and social systems.\u003c/p\u003e \u003cp\u003eWe identified three cases with \u003cem\u003eWFDC2\u003c/em\u003e variants. Therefore, further research involving other Japanese cohorts is warranted to generalize and conduct more detailed findings and geographical analysis. Because \u003cem\u003eWFDC2\u003c/em\u003e variants cause severe bronchiectasis in young individuals, the development of specific drugs targeting this variant is encouraged, in addition to ongoing efforts to treat PCD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors state that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eM.I. and K.M. collected the clinical data and wrote the manuscript. M.H. and N.K. designed the study, analyzed the data, and revised the manuscript. H.H. provided the clinical data. K.W. and A.M. analyzed the data. All the authors critically read and commented on the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images, and this study was approved by the institutional review board of Fukujuji Hospital (#24018).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was funded by the Health, Labor, and Welfare Science Research Grants-in-Aid for Intractable Diseases under \u0026ldquo;Research on diffuse lung diseases\u0026rdquo;, as well as JSPS KAKENHI (Grant Numbers JP22K08297 and JP23K07616).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAra\u0026uacute;jo D, Shteinberg M, Aliberti S, Goeminne PC, Hill AT, Fardon T, Obradovic D, Dimakou K, Polverino E, De Soyza A, McDonnell MJ, Chalmers JD (2017) Standardised classification of the aetiology of bronchiectasis using an objective algorithm. Eur Respir J. ; 50\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYu I, Yong SJ, Lee WY, Kim SH, Lee H, Na JO, Kim DK, Oh YM, Lee JH (2022) Prevalence of chronic rhinosinusitis and its relating factors in patients with bronchiectasis: findings from KMBARC registry. Korean J Intern Med 37:1002\u0026ndash;1010\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim SL, Schwartz BS, Vu TH, Conley DB, Grammer LC, Guo A, Kato A, Kern RC, Prickett MH, Schleimer RP, Smith S, Stevens WW, Suh L, Tan BK, Welch KC, Peters AT (2024) Associations Between Chronic Rhinosinusitis and the Development of Non-Cystic Fibrosis Bronchiectasis. J Allergy Clin Immunol Pract 12:3116\u0026ndash;22e2\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallmeier J, Nielsen KG, Kuehni CE, Lucas JS, Leigh MW, Zariwala MA, Omran H (2020) Motile ciliopathies. Nat Rev Dis Primers 6:77\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShoemark A, Griffin H, Wheway G, Hogg C, Lucas JS, Camps C, Taylor J, Carroll M, Loebinger MR, Chalmers JD, Morris-Rosendahl D, Mitchison HM, De Soyza A, Brown D, Ambrose JC, Arumugam P, Bevers R, Bleda M, Boardman-Pretty F, Boustred CR, Brittain H, Caulfield MJ, Chan GC, Fowler T, Giess A, Hamblin A, Henderson S, Hubbard TJP, Jackson R, Jones LJ, Kasperaviciute D, Kayikci M, Kousathanas A, Lahnstein L, Leigh SEA, Leong IUS, Lopez FJ, Maleady-Crowe F, McEntagart M, Minneci F, Moutsianas L, Mueller M, Murugaesu N, Need AC, O'Donovan P, Odhams CA, Patch C, Perez-Gil D, Pereira MB, Pullinger J, Rahim T, Rendon A, Rogers T, Savage K, Sawant K, Scott RH, Siddiq A, Sieghart A, Smith SC, Sosinsky A, Stuckey A, Tanguy M, Taylor Tavares AL, Thomas ERA, Thompson SR, Tucci A, Welland MJ, Williams E, Witkowska K, Wood SM (2022) Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis. Eur Respir J. ; 60\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun J, Yang L, Lu Y, Wang H, Peng X, Dong X, Cheng G, Cao Y, Wu B, Wang X, Zhou W (2020) Screening for primary immunodeficiency diseases by next-generation sequencing in early life. Clin Transl Immunol 9:e1138\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGuan WJ, Li JC, Liu F, Zhou J, Liu YP, Ling C, Gao YH, Li HM, Yuan JJ, Huang Y, Chen CL, Chen RC, Zhang X, Zhong NS (2018) Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis 10:2618\u0026ndash;2630\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShapiro AJ, Davis SD, Leigh MW, Knowles MR, Lavergne V, Ferkol T (2020) Limitations of Nasal Nitric Oxide Testing in Primary Ciliary Dyskinesia. Am J Respir Crit Care Med 202:476\u0026ndash;477\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakajima K, Ono M, Radović U, Dizdarević S, Tomizawa SI, Kuroha K, Nagamatsu G, Hoshi I, Matsunaga R, Shirakawa T, Kurosawa T, Miyazaki Y, Seki M, Suzuki Y, Koseki H, Nakamura M, Suda T, Ohbo K (2019) Lack of whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (WFDC2) causes neonatal death from respiratory failure in mice. Dis Model Mech. ; 12\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDougherty GW, Ostrowski LE, N\u0026ouml;the-Menchen T, Raidt J, Schramm A, Olbrich H, Yin W, Sears PR, Dang H, Smith AJ, Beule AG, Hjeij R, Rutjes N, Haarman EG, Maas SM, Ferkol TW, Noone PG, Olivier KN, Bracht DC, Barbry P, Zaragosi LE, Fierville M, Kliesch S, Wohlgemuth K, K\u0026ouml;nig J, George S, Loges NT, Ceppe A, Markovetz MR, Luo H, Guo T, Rizk H, Eldesoky T, Dahlke K, Boldt K, Ueffing M, Hill DB, Pang YP, Knowles MR, Zariwala MA, Omran H (2024) Recessively Inherited Deficiency of Secreted WFDC2 (HE4) Causes Nasal Polyposis and Bronchiectasis. Am J Respir Crit Care Med 210:63\u0026ndash;76\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoh JW, Oh J, Kim SJ, Hong JW, Ohk J, Shim HS, Cho H-J, Woo A, Kim SY, Jung H (2024) The founder missense mutation of WFDC2 leads to severe respiratory distress accompanied by bronchiectasis and rhinosinusitis. medRxiv. : 2024.11. 16.24317083.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorimoto K, Hijikata M, Zariwala MA, Nykamp K, Inaba A, Guo TC, Yamada H, Truty R, Sasaki Y, Ohta K, Kudoh S, Leigh MW, Knowles MR, Keicho N (2019) Recurring large deletion in DRC1 (CCDC164) identified as causing primary ciliary dyskinesia in two Asian patients. Mol Genet Genomic Med 7:e838\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHijikata M, Morimoto K, Ito M, Wakabayashi K, Miyabayashi A, Yamada H, Keicho N (2025) Genetic Variants Supporting the Diagnosis of Primary Ciliary Dyskinesia in Japan. Clin Genet 107:219\u0026ndash;223\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatt AP, Sharp JA, Lefevre C, Nicholas KR (2012) WFDC2 is differentially expressed in the mammary gland of the tammar wallaby and provides immune protection to the mammary gland and the developing pouch young. Dev Comp Immunol 36:584\u0026ndash;590\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuriyama S, Yaegashi N, Nagami F, Arai T, Kawaguchi Y, Osumi N, Sakaida M, Suzuki Y, Nakayama K, Hashizume H, Tamiya G, Kawame H, Suzuki K, Hozawa A, Nakaya N, Kikuya M, Metoki H, Tsuji I, Fuse N, Kiyomoto H, Sugawara J, Tsuboi A, Egawa S, Ito K, Chida K, Ishii T, Tomita H, Taki Y, Minegishi N, Ishii N, Yasuda J, Igarashi K, Shimizu R, Nagasaki M, Koshiba S, Kinoshita K, Ogishima S, Takai-Igarashi T, Tominaga T, Tanabe O, Ohuchi N, Shimosegawa T, Kure S, Tanaka H, Ito S, Hitomi J, Tanno K, Nakamura M, Ogasawara K, Kobayashi S, Sakata K, Satoh M, Shimizu A, Sasaki M, Endo R, Sobue K (2016) Tohoku Medical Megabank Project Study Group T, Yamamoto M. The Tohoku Medical Megabank Project: Design and Mission. J Epidemiol 26:493\u0026ndash;511\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u0026nbsp;\u003c/strong\u003eLiterature review on clinical findings in patients with \u003cem\u003eWFDC2\u003c/em\u003e variants, including the present cases.\u003c/p\u003e\n\u003cp\u003eFRC-48, FRC-104, and FRC-191 were cases from Fukujuji Hospital in Japan. UNC-376 II1, OP-2147 II1, OP-2032 II1, OP-1837 II1, OP-4281 II1, UNC-231 II1, OP-398 II1, UNC-186 II1, UNC-186 II2, CSU-150 II2, and OP-4474 II1 were reported from the United States \u003csup\u003e10\u003c/sup\u003e. P1946-21, P1969-21, P2678-21, P2783-21, P5-21, and P5-22 were reported from Korea \u003csup\u003e11\u003c/sup\u003e.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"775\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cem\u003eWFDC2\u003c/em\u003e vatriants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eAge at testing for \u003cem\u003eWFDC2\u003c/em\u003e variants\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eBronchiectasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNeonatal respiratory distress\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eSinusitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eOtitis media\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNasal nitric oxide (nL/min)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ePercent predicted FEV\u003csub\u003e1\u0026nbsp;\u003c/sub\u003e(%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u003cem\u003eP. aeruginosa\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eInfertility\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eLung transplant\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNumber of cases (%) or median [IQR]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e31 [22, 46]*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eFemale 11/20 (55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e17/18 (94.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e3/6 (50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e20/20 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e9/14 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e13.8 [9.0, 17.1]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e52 [29, 67]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e15/15 (100)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eTotal 3/5 (60), Male 0/2 (0), Female 3/3 (100)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e5/20 (25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eFRC-48\u003c/p\u003e\n \u003cp\u003e(Case 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e15.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e66.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eFRC-104 (Case 2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e52.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eFRC-191 (Case 3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e48.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e39.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eUNC-376 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.2T\u0026gt;A; p.Met1? het. deletion, het.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e16.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eOP-2147 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.145T\u0026gt;C; p.Cys49Arg; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e5.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eOP-2032 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.145T\u0026gt;C; p.Cys49Arg; het. deletion exon 1-2; het.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eOP-1837 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.145T\u0026gt;C; p.Cys49Arg; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e16.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eOP-4281 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.145T\u0026gt;C; p.Cys49Arg; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eUNC-231 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.145T\u0026gt;C; p.Cys49Arg; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e33.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e41.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eOP-398 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.145T\u0026gt;C; p.Cys49Arg; het. c.271G\u0026gt;A; p.Gly91Ser; het.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eUNC-186 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.145T\u0026gt;C; p.Cys49Arg; het. c.307T\u0026gt;C; p.Cys103Arg; het.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eUNC-186 II2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.145T\u0026gt;C; p.Cys49Arg; het. c.307T.C; p.Cys103Arg; het.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e17.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eCSU-150 II2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.307T\u0026gt;C; p.Cys103Arg; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eOP-4474 II1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.326G\u0026gt;A; p.Cys109Tyr; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP1946-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e31\u0026ndash;35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP1969-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e36\u0026ndash;40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP2678-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e46\u0026ndash;50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP2783-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e31\u0026ndash;35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP5-21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e21\u0026ndash;25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eP5-22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003ec.291C\u0026gt;G; p.Cys97Trp; hom.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e21\u0026ndash;25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 60px;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003ehom=homozygous; het=heterozygous; F=female; M=male; N/A=data not available\u003c/p\u003e\n\u003cp\u003e*We calculated it under the assumption that P1946-21 was 31 years old, P1969-21 was 36 years old, P2678-21 was 46 years old, P2783-21 was 31 years old, P5-21 was 21 years old, and P5-22 was 21 years old.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"Respiratory Disease Center, Fukujuji Hospital, Japan Anti-Tuberculosis Association, Tokyo, Japan.","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"noncystic fibrosis bronchiectasis, cystic fibrosis, primary ciliary dyskinesia, WFDC2, sinopulmonary disease","lastPublishedDoi":"10.21203/rs.3.rs-5949796/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5949796/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe report the first three cases of bronchiectasis caused by homozygous \u003cem\u003eWFDC2\u003c/em\u003e variants in Japan. The ages at diagnosis of bronchiectasis were 18, 24, and 16 years, and all patients had a history of chronic sinusitis since childhood. Despite low nasal nitric oxide levels, the radiologic features resembled those of cystic fibrosis, characterized by bronchiectasis predominantly in the upper lobes. All patients experienced frequent exacerbations and respiratory dysfunction, even with long-term macrolide therapy. Consequently, two of the three patients required lung transplantation. Considering the possibility of founder mutations, \u003cem\u003eWFDC2\u003c/em\u003e variants should be included in diagnostic panels for patients with sinopulmonary disease in Asian populations.\u003c/p\u003e","manuscriptTitle":"Severe Bronchiectasis and Chronic Rhinosinusitis Due to Homozygous WFDC2 Variants: The First Three Cases Reported from Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-05 11:46:41","doi":"10.21203/rs.3.rs-5949796/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2b4106e6-8501-4ca0-8577-3210569c9241","owner":[],"postedDate":"February 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-28T14:28:03+00:00","versionOfRecord":{"articleIdentity":"rs-5949796","link":"https://doi.org/10.1016/j.rmcr.2025.102214","journal":{"identity":"respiratory-medicine-case-reports","isVorOnly":true,"title":"Respiratory Medicine Case Reports"},"publishedOn":"2025-04-22 00:00:00","publishedOnDateReadable":"April 22nd, 2025"},"versionCreatedAt":"2025-02-05 11:46:41","video":"","vorDoi":"10.1016/j.rmcr.2025.102214","vorDoiUrl":"https://doi.org/10.1016/j.rmcr.2025.102214","workflowStages":[]},"version":"v1","identity":"rs-5949796","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5949796","identity":"rs-5949796","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}