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

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