BACKGROUND: Primary ciliary dyskinesia (PCD) represents a group of rare hereditary disorders characterised by deficient ciliary airway clearance that can be associated with laterality defects. We aimed to describe the underlying gene defects, geographical differences in genotypes and their relationship to diagnostic findings and clinical phenotypes. METHODS: Genetic variants and clinical findings (age, sex, body mass index, laterality defects, forced expiratory volume in 1 s (FEV1)) were collected from 19 countries using the European Reference Network's ERN-LUNG international PCD Registry. Genetic data were evaluated according to American College of Medical Genetics and Genomics guidelines. We assessed regional distribution of implicated genes and genetic variants as well as genotype correlations with laterality defects and FEV1. RESULTS: The study included 1236 individuals carrying 908 distinct pathogenic DNA variants in 46 PCD genes. We found considerable variation in the distribution of PCD genotypes across countries due to the presence of distinct founder variants. The prevalence of PCD genotypes associated with pathognomonic ultrastructural defects (mean 72%, range 47-100%) and laterality defects (mean 42%, range 28-69%) varied widely among countries. The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). The PCD cohort had a reduced median FEV1 z-score (-1.66). Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups, while the FEV1 z-score reductions were significantly milder in DNAH11 (-0.83) and ODAD1 (-0.85) variant groups compared to the whole PCD cohort. CONCLUSION: This unprecedented multinational dataset of DNA variants and information on their distribution across countries facilitates interpretation of the genetic epidemiology of PCD and indicates that the genetic variant can predict diagnostic and phenotypic features such as the course of lung function.

Airway Research Center North Lübeck Germany

Berlin Institute of Health at Charité Universitätsmedizin Berlin Berlin Germany

Biomedical Research in End Stage and Obstructive Lung Disease Hannover Hannover Germany

Center for Pediatrics Department of General Pediatrics Adolescent Medicine and Neonatology Medical Center Faculty of Medicine University of Freiburg Freiburg Germany

Centre for Biomedical Network Research on Rare Diseases Instituto de Salud Carlos 3 Madrid Spain

Clinical and Experimental Sciences University of Southampton Faculty of Medicine Southampton UK

Consejo Nacional de Investigaciones Científicas y Técnicas Buenos Aires Argentina

Danish Primary Ciliary Dyskinesia Centre Paediatric Pulmonary Service Department of Paediatrics and Adolescent Medicine Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department Chrometa BREATHE Laboratory Katholieke Universiteit Leuven Leuven Belgium

Department of Clinical Medicine University of Copenhagen Copenhagen Denmark

Department of General Pediatrics University Hospital Muenster Muenster Germany

Department of Human Genetics Hannover Medical School Hannover Germany

Department of Paediatric Pneumology Allergology and Neonatology Hannover Medical School Hannover Germany

Department of Paediatric Respiratory Medicine and Primary Ciliary Dyskinesia Centre Royal Brompton Hospital and National Heart and Lung Institute Imperial College London London UK

Department of Paediatrics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Paediatrics Comenius University in Bratislava Jessenius Faculty of Medicine in Martin Martin Slovakia

Department of Paediatrics University Hospital Leuven Belgium

Department of Paediatrics University Hospital of Pisa Pisa Italy

Department of Pediatric and Adolescent Medicine Pediatrics 3 Medical University Innsbruck Austria

Department of Pediatric and Adolescent Medicine University Hospital Ulm Ulm Germany

Department of Pediatric Pulmonology Marmara University School of Medicine Istanbul Turkey

Department of Pediatric Respiratory Medicine and Allergy Emma Children's Hospital Amsterdam University Medical Centers Amsterdam The Netherlands

Department of Pediatric Respiratory Medicine Immunology and Critical Care Medicine Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Department of Pediatrics and Pediatric Pulmonology Hadassah Hebrew University Medical Center Jerusalem Israel

Department of Pediatrics Faculty of Medicine and University Hospital University of Cologne Cologne Germany

Department of Pediatrics Faculty of Medicine Makassed Hospital Al Quds University East Jerusalem Palestine

Department of Pediatrics Faculty of Medicine Tel Aviv University Tel Aviv Israel

Department of Pediatrics Institution of Clinical Sciences Lund University Lund Sweden

Department of Pediatrics Queen Silvias Children Hospital Sahlgrenska Academy at University of Gothenburg Gothenburg Sweden

Department of Pediatrics University of Alberta Edmonton AB Canada

Department of Pneumology and Cystic Fibrosis Institute of Tuberculosis and Lung Diseases Rabka Poland

Department of Pulmonary Medicine Adult Cystic Fibrosis Center University Hospital Essen Ruhrlandklinik University of Duisburg Essen Essen Germany

Department of Respiratory Diseases University Hospitals Leuven Leuven Belgium

Department of Respiratory Medicine Hannover Medical School Hannover Germany

Department of Translational Medical Sciences Pediatric Pulmonology Federico 2 University Naples Italy

Division of Molecular and Clinical Medicine University of Dundee Ninewells Hospital and Medical School Dundee UK

Division of Pediatric Pulmonology Allergy and Endocrinology Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Division of Pediatric Pulmonology Faculty of Medicine Hacettepe University Ankara Turkey

Faculty of Health Sciences Ben Gurion University of the Negev Beer Sheva Israel

Faculty of Medicine Tel Aviv University Tel Aviv Israel

Genetics and Genomic Medicine Department University College London UCL Great Ormond Street Institute of Child Health London UK

German Center for Lung Research associated partner site Berlin Germany

Human Genetics and Genomic Medicine University of Southampton Faculty of Medicine Southampton UK

Institute of Human Genetics Polish Academy of Sciences Poznan Poland

Institute of Medical Informatics University of Muenster Muenster Germany

Paediatric Department of Allergy and Lung Diseases Oslo University Hospital Oslo Norway

Paediatric Pulmonology Section Department of Paediatrics Vall d'Hebron Hospital Universitari Vall d'Hebron Barcelona Hospital Campus Universitat Autònoma de Barcelona Barcelona Spain

Pediatric Pulmonary Unit Soroka Medical Center Beer Sheva Israel

Pediatric Pulmonology Unit Hospital Archbishop Makarios 3 Nicosia Cyprus

Pneumology and Cystic Fibrosis Unit Academic Department of Pediatrics Bambino Gesù Children's Hospital Rome Italy

Primary Ciliary Dyskinesia Centre University Hospital Southampton NHS Foundation Trust Southampton UK

Pulmonary Division Heart Institute Hospital das Clínicas da Faculdade de São Paulo São Paulo Brazil

Pulmonary Institute Schneider Children's Medical Center of Israel Petach Tikva Israel

Respiratory Center Ricardo Gutiérrez Children's Hospital Buenos Aires Argentina

Respiratory Physiology Laboratory Medical School University of Cyprus Nicosia Cyprus

Royal Brompton and Harefield Hospitals and National Heart and Lung Institute Imperial College London London UK

Section for Lung Medicine Metabolism and Neurology Pediatrics Clinic Skane University Hospital Lund Sweden

Section of Pulmonary Critical Care and Sleep Medicine Department of Internal Medicine Yale University School of Medicine New Haven CT USA

University Children's Hospital Ruhr University Bochum Katholisches Klinikum Bochum Bochum Germany

Wessex Regional Genetics Laboratory Salisbury NHS Foundation Trust Salisbury UK

Komentář v

Eur Respir J. 2024 Aug 8;64(2):2401026. doi: 10.1183/13993003.01026-2024. PubMed

Zobrazit více v PubMed

Wallmeier J, Nielsen KG, Kuehni CE, et al. . Motile ciliopathies. Nat Rev Dis Primers 2020; 6: 77. doi:10.1038/s41572-020-0209-6 PubMed DOI

Pennekamp P, Raidt J, Wohlgemuth K, et al. . Primary ciliary dyskinesia. In: Wagner TOF, Humbert M, Wijsenbeek M, et al., eds. Rare Diseases of the Respiratory System. Sheffield, European Respiratory Society, 2023; pp. 118–134.

Raidt J, Krenz H, Tebbe J, et al. . Limitations of nasal nitric oxide measurement for diagnosis of primary ciliary dyskinesia with normal ultrastructure. Ann Am Thorac Soc 2022; 19: 1275–1284. doi:10.1513/AnnalsATS.202106-728OC PubMed DOI

Shoemark A, Rubbo B, Legendre M, et al. . Topological data analysis reveals genotype–phenotype relationships in primary ciliary dyskinesia. Eur Respir J 2021; 58: 2002359. doi:10.1183/13993003.02359-2020 PubMed DOI

Kinghorn B, Rosenfeld M, Sullivan E, et al. . Airway disease in children with primary ciliary dyskinesia: impact of ciliary ultrastructure defect and genotype. Ann Am Thorac Soc 2023; 20: 539–547. doi:10.1513/AnnalsATS.202206-524OC PubMed DOI PMC

Legendre M, Thouvenin G, Taytard J, et al. . High nasal nitric oxide, cilia analyses, and genotypes in a retrospective cohort of children with primary ciliary dyskinesia. Ann Am Thorac Soc 2022; 19: 1704–1712. doi:10.1513/AnnalsATS.202110-1175OC PubMed DOI

Emiralioğlu N, Taşkıran EZ, Koşukcu C, et al. . Genotype and phenotype evaluation of patients with primary ciliary dyskinesia: first results from Turkey. Pediatr Pulmonol 2020; 55: 383–393. doi:10.1002/ppul.24583 PubMed DOI

Fassad MR, Patel MP, Shoemark A, et al. . Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort. J Med Genet 2020; 57: 322–330. doi:10.1136/jmedgenet-2019-106501 PubMed DOI

Yiallouros PK, Kouis P, Kyriacou K, et al. . Implementation of multigene panel NGS diagnosis in the national primary ciliary dyskinesia cohort of Cyprus: an island with a high disease prevalence. Hum Mutat 2021; 42: e62–e77. doi:10.1002/humu.24196 PubMed DOI

Rumman N, Fassad MR, Driessens C, et al. . The Palestinian primary ciliary dyskinesia population: first results of the diagnostic and genetic spectrum. ERJ Open Res 2023; 9: 00714-2022. doi:10.1183/23120541.00714-2022 PubMed DOI PMC

Werner C, Lablans M, Ataian M, et al. . An international registry for primary ciliary dyskinesia. Eur Respir J 2016; 47: 849–859. doi:10.1183/13993003.00776-2015 PubMed DOI

Ardura-Garcia C, Goutaki M, Carr SB, et al. . Registries and collaborative studies for primary ciliary dyskinesia in Europe. ERJ Open Res 2020; 6: 00005-2020. doi:10.1183/23120541.00005-2020 PubMed DOI PMC

Raidt J, Maitre B, Pennekamp P, et al. . The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN. ERJ Open Res 2022; 8: 00139-2022. doi:10.1183/23120541.00139-2022 PubMed DOI PMC

Richards S, Aziz N, Bale S, et al. . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405–424. doi:10.1038/gim.2015.30 PubMed DOI PMC

Shoemark A, Boon M, Brochhausen C, et al. . International consensus guideline for reporting transmission electron microscopy results in the diagnosis of primary ciliary dyskinesia (BEAT PCD TEM Criteria). Eur Respir J 2020; 55: 1900725. doi:10.1183/13993003.00725-2019 PubMed DOI

Hannah WB, Seifert BA, Truty R, et al. . The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: a genetic database analysis. Lancet Respir Med 2022; 10: 459–468. doi:10.1016/S2213-2600(21)00453-7 PubMed DOI PMC

Hornef N, Olbrich H, Horvath J, et al. . DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med 2006; 174: 120–126. doi:10.1164/rccm.200601-084OC PubMed DOI PMC

Ong T, Ramsey BW. Cystic fibrosis: a review. JAMA 2023; 329: 1859–1871. doi:10.1001/jama.2023.8120 PubMed DOI

Bell SC, Mall MA, Gutierrez H, et al. . The future of cystic fibrosis care: a global perspective. Lancet Respir Med 2020; 8: 65–124. doi:10.1016/S2213-2600(19)30337-6 PubMed DOI PMC

Zariwala MA, Leigh MW, Ceppa F, et al. . Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation. Am J Respir Crit Care Med 2006; 174: 858–866. doi:10.1164/rccm.200603-370OC PubMed DOI PMC

Antony D, Becker-Heck A, Zariwala MA, et al. . Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Hum Mutat 2013; 34: 462–472. doi:10.1002/humu.22261 PubMed DOI PMC

Onoufriadis A, Paff T, Antony D, et al. . Splice-site mutations in the axonemal outer dynein arm docking complex gene CCDC114 cause primary ciliary dyskinesia. Am J Hum Genet 2013; 92: 88–98. doi:10.1016/j.ajhg.2012.11.002 PubMed DOI PMC

Kos R, Israëls J, van Gogh CDL, et al. . Primary ciliary dyskinesia in Volendam: diagnostic and phenotypic features in patients with a CCDC114 mutation. Am J Med Genet C Semin Med Genet 2022; 190: 89–101. doi:10.1002/ajmg.c.31968 PubMed DOI PMC

Djakow J, Kramná L, Dušátková L, et al. . An effective combination of Sanger and next-generation sequencing in diagnostics of primary ciliary dyskinesia. Pediatr Pulmonol 2016; 51: 498–509. doi:10.1002/ppul.23261 PubMed DOI

Knowles MR, Leigh MW, Ostrowski LE, et al. . Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. Am J Hum Genet 2013; 92: 99–106. doi:10.1016/j.ajhg.2012.11.003 PubMed DOI PMC

Panizzi JR, Becker-Heck A, Castleman VH, et al. . CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms. Nat Genet 2012; 44: 714–719. doi:10.1038/ng.2277 PubMed DOI PMC

Shoemark A, Moya E, Hirst RA, et al. . High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations. Thorax 2018; 73: 157–166. doi:10.1136/thoraxjnl-2017-209999 PubMed DOI PMC

Olbrich H, Schmidts M, Werner C, et al. . Recessive HYDIN mutations cause primary ciliary dyskinesia without randomization of left–right body asymmetry. Am J Hum Genet 2012; 91: 672–684. doi:10.1016/j.ajhg.2012.08.016 PubMed DOI PMC

Zietkiewicz E, Bukowy-Bieryllo Z, Rabiasz A, et al. . CFAP300: mutations in Slavic patients with primary ciliary dyskinesia and a role in ciliary dynein arms trafficking. Am J Respir Cell Mol Biol 2019; 61: 440–449. doi:10.1165/rcmb.2018-0260OC PubMed DOI

Höben IM, Hjeij R, Olbrich H, et al. . Mutations in C11orf70 cause primary ciliary dyskinesia with randomization of left/right body asymmetry due to defects of outer and inner dynein arms. Am J Hum Genet 2018; 102: 973–984. doi:10.1016/j.ajhg.2018.03.025 PubMed DOI PMC

Wallmeier J, Al-Mutairi DA, Chen CT, et al. . Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Genet 2014; 46: 646–651. doi:10.1038/ng.2961 PubMed DOI

Amirav I, Wallmeier J, Loges NT, et al. . Systematic analysis of CCNO variants in a defined population: implications for clinical phenotype and differential diagnosis. Hum Mutat 2016; 37: 396–405. doi:10.1002/humu.22957 PubMed DOI

Boon M, Wallmeier J, Ma L, et al. . MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia. Nat Commun 2014; 5: 4418. doi:10.1038/ncomms5418 PubMed DOI

Mazor M, Alkrinawi S, Chalifa-Caspi V, et al. . Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1. Am J Hum Genet 2011; 88: 599–607. doi:10.1016/j.ajhg.2011.03.018 PubMed DOI PMC

Yiallouros PK, Kouis P, Pirpa P, et al. . Wide phenotypic variability in RSPH9-associated primary ciliary dyskinesia: review of a case-series from Cyprus. J Thorac Dis 2019; 11: 2067–2075. doi:10.21037/jtd.2019.04.71 PubMed DOI PMC

Pifferi M, Bush A, Mulé G, et al. . Longitudinal lung volume changes by ultrastructure and genotype in primary ciliary dyskinesia. Ann Am Thorac Soc 2021; 18: 963–970. doi:10.1513/AnnalsATS.202007-816OC PubMed DOI

Frommer A, Hjeij R, Loges NT, et al. . Immunofluorescence analysis and diagnosis of primary ciliary dyskinesia with radial spoke defects. Am J Respir Cell Mol Biol 2015; 53: 563–573. doi:10.1165/rcmb.2014-0483OC PubMed DOI PMC

Boaretto F, Snijders D, Salvoro C, et al. . Diagnosis of primary ciliary dyskinesia by a targeted next-generation sequencing panel: molecular and clinical findings in Italian patients. J Mol Diagn 2016; 18: 912–922. doi:10.1016/j.jmoldx.2016.07.002 PubMed DOI

Moore DJ, Onoufriadis A, Shoemark A, et al. . Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia. Am J Hum Genet 2013; 93: 346–356. doi:10.1016/j.ajhg.2013.07.009 PubMed DOI PMC

Lucas JS, Barbato A, Collins SA, et al. . European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia. Eur Respir J 2017; 49: 1601090. doi:10.1183/13993003.01090-2016 PubMed DOI PMC

Shapiro AJ, Davis SD, Polineni D, et al. . Diagnosis of primary ciliary dyskinesia. an official American Thoracic Society clinical practice guideline. Am J Respir Crit Care Med 2018; 197: e24–e39. doi:10.1164/rccm.201805-0819ST PubMed DOI PMC

Kouis P, Yiallouros PK, Middleton N, et al. . Prevalence of primary ciliary dyskinesia in consecutive referrals of suspect cases and the transmission electron microscopy detection rate: a systematic review and meta-analysis. Pediatr Res 2017; 81: 398–405. doi:10.1038/pr.2016.263 PubMed DOI

Shah A, Shoemark A, MacNeill SJ, et al. . A longitudinal study characterising a large adult primary ciliary dyskinesia population. Eur Respir J 2016; 48: 441–450. doi:10.1183/13993003.00209-2016 PubMed DOI

Goutaki M, Pedersen ESL. Phenotype–genotype associations in primary ciliary dyskinesia: where do we stand? Eur Respir J 2021; 58: 2100392. doi:10.1183/13993003.00392-2021 PubMed DOI

Halbeisen FS, Jose A, de Jong C, et al. . Spirometric indices in primary ciliary dyskinesia: systematic review and meta-analysis. ERJ Open Res 2019; 5: 00231-2018. doi:10.1183/23120541.00231-2018 PubMed DOI PMC

Sayitoğlu M. Clinical interpretation of genomic variations. Turk J Haematol 2016; 33: 172–179. doi:10.4274/tjh.2016.0149 PubMed DOI PMC

Mall MA, Mayer-Hamblett N, Rowe SM. Cystic fibrosis: emergence of highly effective targeted therapeutics and potential clinical implications. Am J Respir Crit Care Med 2020; 201: 1193–1208. doi:10.1164/rccm.201910-1943SO PubMed DOI PMC

Barry PJ, Mall MA, Álvarez A, et al. . Triple therapy for cystic fibrosis Phe508del-gating and -residual function genotypes. N Engl J Med 2021; 385: 815–825. doi:10.1056/NEJMoa2100665 PubMed DOI PMC

Middleton PG, Mall MA, Dřevínek P, et al. . Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med 2019; 381: 1809–1819. doi:10.1056/NEJMoa1908639 PubMed DOI PMC

Paff T, Omran H, Nielsen KG, et al. . Current and future treatments in primary ciliary dyskinesia. Int J Mol Sci 2021; 22: 9834. doi:10.3390/ijms22189834 PubMed DOI PMC

Kennedy MP, Omran H, Leigh MW, et al. . Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia. Circulation 2007; 115: 2814–2821. doi:10.1161/CIRCULATIONAHA.106.649038 PubMed DOI

Shapiro AJ, Davis SD, Ferkol T, et al. . Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy. Chest 2014; 146: 1176–1186. doi:10.1378/chest.13-1704 PubMed DOI PMC

Barber AT, Shapiro AJ, Davis SD, et al. . Laterality defects in primary ciliary dyskinesia: relationship to ultrastructural defect or genotype. Ann Am Thorac Soc 2023; 20: 397–405. doi:10.1513/AnnalsATS.202206-487OC PubMed DOI PMC

Kuehni CE, Frischer T, Strippoli MP, et al. . Factors influencing age at diagnosis of primary ciliary dyskinesia in European children. Eur Respir J 2010; 36: 1248–1258. doi:10.1183/09031936.00001010 PubMed DOI

Pifferi M, Bush A, Mariani F, et al. . Lung function longitudinal study by phenotype and genotype in primary ciliary dyskinesia. Chest 2020; 158: 117–120. doi:10.1016/j.chest.2020.02.001 PubMed DOI

Davis SD, Rosenfeld M, Lee HS, et al. . Primary ciliary dyskinesia: longitudinal study of lung disease by ultrastructure defect and genotype. Am J Respir Crit Care Med 2019; 199: 190–198. doi:10.1164/rccm.201803-0548OC PubMed DOI PMC

Frija-Masson J, Bassinet L, Honoré I, et al. . Clinical characteristics, functional respiratory decline and follow-up in adult patients with primary ciliary dyskinesia. Thorax 2017; 72: 154–160. doi:10.1136/thoraxjnl-2015-207891 PubMed DOI

Davis SD, Ferkol TW, Rosenfeld M, et al. . Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype. Am J Respir Crit Care Med 2015; 191: 316–324. doi:10.1164/rccm.201409-1672OC PubMed DOI PMC

Roehmel JF, Doerfler FJ, Koerner-Rettberg C, et al. . Comparison of the lung clearance index in preschool children with primary ciliary dyskinesia and cystic fibrosis. Chest 2022; 162: 534–542. doi:10.1016/j.chest.2022.02.052 PubMed DOI

Irving S, Dixon M, Fassad MR, et al. . Primary ciliary dyskinesia due to microtubular defects is associated with worse lung clearance index. Lung 2018; 196: 231–238. doi:10.1007/s00408-018-0086-x PubMed DOI PMC

Knowles MR, Ostrowski LE, Leigh MW, et al. . Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype. Am J Respir Crit Care Med 2014; 189: 707–717. doi:10.1164/rccm.201311-2047OC PubMed DOI PMC

Primary ciliary dyskinesia as a rare cause of male infertility: case report and literature overview