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

Justyna A. Karolak, Marie Vincent, Gail Deutsch, Tomasz Gambin, Benjamin Cogné, Olivier Pichon, Francesco Vetrini, Heather C. Mefford, 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. BoerkoelTina M. Bartell, Catherine Ward-Melver, Thomas Besnard, Florence Petit, Iben Bache, Zeynep Tümer, Marie Denis-Musquer, Madeleine Joubert, Jelena Martinovic, Claire Bénéteau, Arnaud Molin, Dominique Carles, Gwenaelle André, Eric Bieth, Nicolas Chassaing, Louise Devisme, Lara Chalabreysse, Laurent Pasquier, Véronique Secq, Massimiliano Don, Maria Orsaria, Chantal Missirian, Jérémie Mortreux, Damien Sanlaville, Linda Pons, Sébastien Küry, Stéphane Bézieau, Jean Michel Liet, Nicolas Joram, Tiphaine Bihouée, 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, Galen M. Schauer, Mark H. Lipson, Catherine L. Mercer, Arie van Haeringen, Qian Liu, Edwina Popek, Zeynep H. Coban Akdemir, James R. Lupski, Przemyslaw Szafranski, Bertrand Isidor, Cedric Le Caignec, Paweł Stankiewicz

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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 ∼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.

Original languageEnglish
Pages (from-to)213-228
Number of pages16
JournalAmerican journal of human genetics
Issue number2
StatePublished - Feb 7 2019


  • 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


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