Journal articles

Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

Justyna A. Karolak ¹ Marie Vincent ^{2, 3} Gail Deutsch ⁴ Tomasz Gambin ⁵ Benjamin Cogne ^{2, 3} Olivier Pichon ⁶ Francesco Vetrini ⁷ Heather C. Mefford ⁸ Jennifer N. Dines ⁸ Katie Golden-Grant ⁴ Katrina Dipple ⁸ Amanda S. Freed ⁸ Kathleen A. Leppig ⁹ Megan Dishop ¹⁰ David Mowat ¹¹ Bruce Bennetts ¹² Andrew J. Gifford ¹³ Martin A. Weber ¹⁴ Anna F. Lee ¹⁵ Cornelius F. Boerkoel ¹⁵ Tina M. Bartell ⁹ Catherine Ward-Melver ¹⁶ Thomas Besnard ³ Florence Petit ¹⁷ Iben Bache ¹⁸ Zeynep Tumer ¹⁹ Marie Denis-Musquer ² Madeleine Joubert ² Jelena Martinovic ²⁰ Claire Beneteau ⁶ Arnaud Molin ^{21, 22} Dominique Carles ^{23, 24} Gwenaelle Andre ²⁴ Eric Bieth ^{25, 26} Nicolas Chassaing ^{25, 26} Louise Devisme ²⁷ Lara Chalabreysse ²⁸ Laurent Pasquier ^{29, 30} Veronique Secq ³¹ Massimiliano Don ³² Maria Orsaria ³³ Chantal Missirian ³⁴ Jeremie Mortreux ^{34, 35} Damien Sanlaville ³⁶ Linda Pons ³⁶ Sebastien Kury ^{6, 3} Stephane Bezieau ^{3, 6} Jean-Michel Liet ² Nicolas Joram ² Tiphaine Bihouee ³ Daryl A. Scott ⁷ Chester W. Brown ³⁷ Fernando Scaglia ³⁸ Anne Chun-Hui Tsai ³⁹ Dorothy K. Grange ⁴⁰ John A. Phillips ⁴¹ Jean P. Pfotenhauer ⁴¹ Shalini N. Jhangiani ⁷ Claudia G. Gonzaga-Jauregui ⁴² Wendy K. Chung ⁴³ Galen M. Schauer ⁹ Mark H. Lipson ⁹ Catherine L. Mercer ⁴⁴ Arie Van Haeringen ⁴⁵ Qian Liu ³⁸ Edwina Popek ³⁸ Zeynep H. Coban Akdemir ³⁸ James R. Lupski ³⁸ Przemyslaw Szafranski ⁷ Bertrand Isidor ^{6, 3} Cedric Le Caignec ⁶ Pawe Stankiewicz

1 PUMS - Poznan University of Medical Sciences [Poland]

2 CHU Nantes - Centre hospitalier universitaire de Nantes

3 ITX - unité de recherche de l'institut du thorax UMR1087 UMR6291

4 Seattle Children’s Hospital

5 Institute of Mother and Child

6 Service de génétique médicale - Unité de génétique clinique [Nantes]

7 Baylor College of Medecine

8 University of Washington [Seattle]

9 Kaiser Permanente

10 Phoenix Children's Hospital

11 Sydney Children's hospital

12 The University of Sydney

13 The University of Sydney

14 Prince of Wales Hospital

15 UBC - University of British Columbia

16 Akron Children's Hospital

17 Laboratoire de dynamique des systèmes neuroendocriniens

18 UCPH - University of Copenhagen = Københavns Universitet

19 Copenhagen University Hospital

20 AP-HP - Hôpital Antoine Béclère [Clamart]

21 Service de Génétique [CHU Caen]

22 BIOTARGEN - Biologie, génétique et thérapies ostéoarticulaires et respiratoires

23 Université Bordeaux Segalen - Bordeaux 2

24 CHU Bordeaux [Bordeaux]

25 UDEAR - Unité différenciation épidermique et auto-immunité rhumatoïde

26 CHU Toulouse [Toulouse]

27 CHU Lille

28 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]

29 Service de génétique clinique [Rennes]

30 ANTICIPE - Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers

31 APHM - Assistance Publique - Hôpitaux de Marseille

32 Sant’Antonio General Hospital

33 Università degli Studi di Udine - University of Udine [Italie]

34 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille

35 Département de génétique médicale [Hôpital de la Timone - APHM]

36 Université de Lyon

37 UTHSC - The University of Tennessee Health Science Center [Memphis]

38 BCM - Baylor College of Medicine

39 UCCS - University of Colorado [Colorado Springs]

40 Washington University School of Medicine in St. Louis

41 Vanderbilt University Medical Center [Nashville]

42 Regeneron Pharmaceuticals [Tarrytown]

43 Mizzou - University of Missouri [Columbia]

44 University Hospital Southampton NHS Foundation Trust

45 Leiden University

Abstract : Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping similar to 2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

Keywords : 17q23.1q23.2 recurrent deletion 5p12 deletion T-box transcription factor 4 aplasia of lacrimal and salivary glands fibroblast growth factor 10 lacrimoauriculodentodigital (LAAD) syndrome lung hypoplasia neonatal lung disease

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Genetics

Complete list of metadata

https://hal-amu.archives-ouvertes.fr/hal-02461467
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Submitted on : Thursday, January 30, 2020 - 4:36:18 PM
Last modification on : Friday, August 5, 2022 - 12:31:37 PM