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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 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
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.
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Submitted on : Thursday, January 30, 2020 - 4:36:18 PM
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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, Elsevier (Cell Press), 2019, 104 (2), pp.213-228. ⟨10.1016/j.ajhg.2018.12.010⟩. ⟨hal-02461467⟩

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