Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations

Johanna Raidt; Sarah Riepenhausen; Petra Pennekamp; Heike Olbrich; Israel Amirav; Rodrigo A. Athanazio; Micha Aviram; Juan E. Balinotti; Ophir Bar-On; Sebastian F.N. Bode; Mieke Boon; Melissa Borrelli; Siobhan B. Carr; Suzanne Crowley; Eleonora Dehlink; Sandra Diepenhorst; Peter Durdik; Bernd Dworniczak; Nagehan Emiralioğlu; Ela Erdem; Rossella Fonnesu; Serena Gracci; Jörg Große-Onnebrink; Karolina Gwozdziewicz; Eric G. Haarman; Christine R. Hansen; Claire Hogg; Mathias G. Holgersen; Eitan Kerem Robert W. Körner; Karsten Kötz; Panayiotis Kouis; Michael R. Loebinger; Natalie Lorent; Jane S. Lucas; Debora Maj; Marcus A. Mall; June K. Marthin; Vendula Martinu; Henryk Mazurek; Hannah M. Mitchison; Tabea Nöthe-Menchen; Ugur Özçelik; Massimo Pifferi; Andrzej Pogorzelski; Felix C. Ringshausen; Jobst F. Roehmel; Sandra Rovira-Amigo; Nisreen Rumman; Anne Schlegtendal; Amelia Shoemark; Synne Sperstad Kennelly; Ben O. Staar; Sivagurunathan Sutharsan; Simon Thomas; Nicola Ullmann; Julian Varghese; Sandra von Hardenberg; Woolf T. Walker; Martin Wetzke; Michal Witt; Panayiotis Yiallouros; Anna Zschocke; Ewa Ziętkiewicz; Kim G. Nielsen; Heymut Omran

doi:10.1183/13993003.01769-2023

Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations

Johanna Raidt, Sarah Riepenhausen, Petra Pennekamp, Heike Olbrich, Israel Amirav, Rodrigo A. Athanazio, Micha Aviram, Juan E. Balinotti, Ophir Bar-On, Sebastian F.N. Bode, Mieke Boon, Melissa Borrelli, Siobhan B. Carr, Suzanne Crowley, Eleonora Dehlink, Sandra Diepenhorst, Peter Durdik, Bernd Dworniczak, Nagehan Emiralioğlu, Ela ErdemRossella Fonnesu, Serena Gracci, Jörg Große-Onnebrink, Karolina Gwozdziewicz, Eric G. Haarman, Christine R. Hansen, Claire Hogg, Mathias G. Holgersen, Eitan Kerem Robert W. Körner, Karsten Kötz, Panayiotis Kouis, Michael R. Loebinger, Natalie Lorent, Jane S. Lucas, Debora Maj, Marcus A. Mall, June K. Marthin, Vendula Martinu, Henryk Mazurek, Hannah M. Mitchison, Tabea Nöthe-Menchen, Ugur Özçelik, Massimo Pifferi, Andrzej Pogorzelski, Felix C. Ringshausen, Jobst F. Roehmel, Sandra Rovira-Amigo, Nisreen Rumman, Anne Schlegtendal, Amelia Shoemark, Synne Sperstad Kennelly, Ben O. Staar, Sivagurunathan Sutharsan, Simon Thomas, Nicola Ullmann, Julian Varghese, Sandra von Hardenberg, Woolf T. Walker, Martin Wetzke, Michal Witt, Panayiotis Yiallouros, Anna Zschocke, Ewa Ziętkiewicz, Kim G. Nielsen, Heymut Omran

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Abstract

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.

Original language	English
Article number	2301769
Journal	European Respiratory Journal
Volume	64
Issue number	2
DOIs	https://doi.org/10.1183/13993003.01769-2023
State	Published - 2024
Externally published	Yes

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© 2024 European Respiratory Society. All rights reserved.

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10.1183/13993003.01769-2023

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Raidt, J., Riepenhausen, S., Pennekamp, P., Olbrich, H., Amirav, I., Athanazio, R. A., Aviram, M., Balinotti, J. E., Bar-On, O., Bode, S. F. N., Boon, M., Borrelli, M., Carr, S. B., Crowley, S., Dehlink, E., Diepenhorst, S., Durdik, P., Dworniczak, B., Emiralioğlu, N., ... Omran, H. (2024). Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations. European Respiratory Journal, 64(2), Article 2301769. https://doi.org/10.1183/13993003.01769-2023

@article{f08e8d127e1247fcb0d8630715d6247a,

title = "Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations",

abstract = "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{\textquoteright}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.",

author = "Johanna Raidt and Sarah Riepenhausen and Petra Pennekamp and Heike Olbrich and Israel Amirav and Athanazio, {Rodrigo A.} and Micha Aviram and Balinotti, {Juan E.} and Ophir Bar-On and Bode, {Sebastian F.N.} and Mieke Boon and Melissa Borrelli and Carr, {Siobhan B.} and Suzanne Crowley and Eleonora Dehlink and Sandra Diepenhorst and Peter Durdik and Bernd Dworniczak and Nagehan Emiralioğlu and Ela Erdem and Rossella Fonnesu and Serena Gracci and J{\"o}rg Gro{\ss}e-Onnebrink and Karolina Gwozdziewicz and Haarman, {Eric G.} and Hansen, {Christine R.} and Claire Hogg and Holgersen, {Mathias G.} and K{\"o}rner, {Eitan Kerem Robert W.} and Karsten K{\"o}tz and Panayiotis Kouis and Loebinger, {Michael R.} and Natalie Lorent and Lucas, {Jane S.} and Debora Maj and Mall, {Marcus A.} and Marthin, {June K.} and Vendula Martinu and Henryk Mazurek and Mitchison, {Hannah M.} and Tabea N{\"o}the-Menchen and Ugur {\"O}z{\c c}elik and Massimo Pifferi and Andrzej Pogorzelski and Ringshausen, {Felix C.} and Roehmel, {Jobst F.} and Sandra Rovira-Amigo and Nisreen Rumman and Anne Schlegtendal and Amelia Shoemark and Kennelly, {Synne Sperstad} and Staar, {Ben O.} and Sivagurunathan Sutharsan and Simon Thomas and Nicola Ullmann and Julian Varghese and {von Hardenberg}, Sandra and Walker, {Woolf T.} and Martin Wetzke and Michal Witt and Panayiotis Yiallouros and Anna Zschocke and Ewa Zi{\c e}tkiewicz and Nielsen, {Kim G.} and Heymut Omran",

year = "2024",

doi = "10.1183/13993003.01769-2023",

language = "אנגלית",

volume = "64",

journal = "European Respiratory Journal",

issn = "0903-1936",

publisher = "European Respiratory Society",

number = "2",

}

Raidt, J, Riepenhausen, S, Pennekamp, P, Olbrich, H, Amirav, I, Athanazio, RA, Aviram, M, Balinotti, JE, Bar-On, O, Bode, SFN, Boon, M, Borrelli, M, Carr, SB, Crowley, S, Dehlink, E, Diepenhorst, S, Durdik, P, Dworniczak, B, Emiralioğlu, N, Erdem, E, Fonnesu, R, Gracci, S, Große-Onnebrink, J, Gwozdziewicz, K, Haarman, EG, Hansen, CR, Hogg, C, Holgersen, MG, Körner, EKRW, Kötz, K, Kouis, P, Loebinger, MR, Lorent, N, Lucas, JS, Maj, D, Mall, MA, Marthin, JK, Martinu, V, Mazurek, H, Mitchison, HM, Nöthe-Menchen, T, Özçelik, U, Pifferi, M, Pogorzelski, A, Ringshausen, FC, Roehmel, JF, Rovira-Amigo, S, Rumman, N, Schlegtendal, A, Shoemark, A, Kennelly, SS, Staar, BO, Sutharsan, S, Thomas, S, Ullmann, N, Varghese, J, von Hardenberg, S, Walker, WT, Wetzke, M, Witt, M, Yiallouros, P, Zschocke, A, Ziętkiewicz, E, Nielsen, KG & Omran, H 2024, 'Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations', European Respiratory Journal, vol. 64, no. 2, 2301769. https://doi.org/10.1183/13993003.01769-2023

TY - JOUR

T1 - Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations

AU - Raidt, Johanna

AU - Riepenhausen, Sarah

AU - Pennekamp, Petra

AU - Olbrich, Heike

AU - Amirav, Israel

AU - Athanazio, Rodrigo A.

AU - Aviram, Micha

AU - Balinotti, Juan E.

AU - Bar-On, Ophir

AU - Bode, Sebastian F.N.

AU - Boon, Mieke

AU - Borrelli, Melissa

AU - Carr, Siobhan B.

AU - Crowley, Suzanne

AU - Dehlink, Eleonora

AU - Diepenhorst, Sandra

AU - Durdik, Peter

AU - Dworniczak, Bernd

AU - Emiralioğlu, Nagehan

AU - Erdem, Ela

AU - Fonnesu, Rossella

AU - Gracci, Serena

AU - Große-Onnebrink, Jörg

AU - Gwozdziewicz, Karolina

AU - Haarman, Eric G.

AU - Hansen, Christine R.

AU - Hogg, Claire

AU - Holgersen, Mathias G.

AU - Körner, Eitan Kerem Robert W.

AU - Kötz, Karsten

AU - Kouis, Panayiotis

AU - Loebinger, Michael R.

AU - Lorent, Natalie

AU - Lucas, Jane S.

AU - Maj, Debora

AU - Mall, Marcus A.

AU - Marthin, June K.

AU - Martinu, Vendula

AU - Mazurek, Henryk

AU - Mitchison, Hannah M.

AU - Nöthe-Menchen, Tabea

AU - Özçelik, Ugur

AU - Pifferi, Massimo

AU - Pogorzelski, Andrzej

AU - Ringshausen, Felix C.

AU - Roehmel, Jobst F.

AU - Rovira-Amigo, Sandra

AU - Rumman, Nisreen

AU - Schlegtendal, Anne

AU - Shoemark, Amelia

AU - Kennelly, Synne Sperstad

AU - Staar, Ben O.

AU - Sutharsan, Sivagurunathan

AU - Thomas, Simon

AU - Ullmann, Nicola

AU - Varghese, Julian

AU - von Hardenberg, Sandra

AU - Walker, Woolf T.

AU - Wetzke, Martin

AU - Witt, Michal

AU - Yiallouros, Panayiotis

AU - Zschocke, Anna

AU - Ziętkiewicz, Ewa

AU - Nielsen, Kim G.

AU - Omran, Heymut

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85194899923&partnerID=8YFLogxK

U2 - 10.1183/13993003.01769-2023

DO - 10.1183/13993003.01769-2023

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 38871375

AN - SCOPUS:85194899923

SN - 0903-1936

VL - 64

JO - European Respiratory Journal

JF - European Respiratory Journal

IS - 2

M1 - 2301769

ER -

Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype–phenotype correlations

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