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-lab - Unité de recherche de l'institut du thorax
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 - Centre Hospitalier Universitaire de 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

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

Domains: Life Sciences [q-bio]; Genetics

Justyna A. Karolak, Marie Vincent, Gail Deutsch, Tomasz Gambin, Benjamin Cogne, et al.. Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway. American Journal of Human Genetics, 2019, 104 (2), pp.213-228. ⟨10.1016/j.ajhg.2018.12.010⟩. ⟨hal-02461467⟩