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

American journal of human genetics, 2019-02, Vol.104 (2), p.213-228 [Peer Reviewed Journal]

2018 American Society of Human Genetics ;Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. ;Distributed under a Creative Commons Attribution 4.0 International License ;2018 American Society of Human Genetics. 2018 American Society of Human Genetics ;ISSN: 0002-9297 ;EISSN: 1537-6605 ;DOI: 10.1016/j.ajhg.2018.12.010 ;PMID: 30639323

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Title:
Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway
Author: Karolak, Justyna A. ; Vincent, Marie ; Deutsch, Gail ; Gambin, Tomasz ; Cogné, Benjamin ; Pichon, Olivier ; Vetrini, Francesco ; Mefford, Heather C. ; Dines, Jennifer N. ; Golden-Grant, Katie ; Dipple, Katrina ; Freed, Amanda S. ; Leppig, Kathleen A. ; Dishop, Megan ; Mowat, David ; Bennetts, Bruce ; Gifford, Andrew J. ; Weber, Martin A. ; Lee, Anna F. ; Boerkoel, Cornelius F. ; Bartell, Tina M. ; Ward-Melver, Catherine ; Besnard, Thomas ; Petit, Florence ; Bache, Iben ; Tümer, Zeynep ; Denis-Musquer, Marie ; Joubert, Madeleine ; Martinovic, Jelena ; Bénéteau, Claire ; Molin, Arnaud ; Carles, Dominique ; André, Gwenaelle ; Bieth, Eric ; Chassaing, Nicolas ; Devisme, Louise ; Chalabreysse, Lara ; Pasquier, Laurent ; Secq, Véronique ; Don, Massimiliano ; Orsaria, Maria ; Missirian, Chantal ; Mortreux, Jérémie ; Sanlaville, Damien ; Pons, Linda ; Küry, Sébastien ; Bézieau, Stéphane ; Liet, Jean-Michel ; Joram, Nicolas ; Bihouée, Tiphaine ; Scott, Daryl A. ; Brown, Chester W. ; Scaglia, Fernando ; Tsai, Anne Chun-Hui ; Grange, Dorothy K. ; Phillips, John A. ; Pfotenhauer, Jean P. ; Jhangiani, Shalini N. ; Gonzaga-Jauregui, Claudia G. ; Chung, Wendy K. ; Schauer, Galen M. ; Lipson, Mark H. ; Mercer, Catherine L. ; van Haeringen, Arie ; Liu, Qian ; Popek, Edwina ; Coban Akdemir, Zeynep H. ; Lupski, James R. ; Szafranski, Przemyslaw ; Isidor, Bertrand ; Le Caignec, Cedric ; Stankiewicz, Paweł
Subjects: 17q23.1q23.2 recurrent deletion ; 5p12 deletion ; aplasia of lacrimal and salivary glands ; DNA Copy Number Variations - genetics ; Female ; fibroblast growth factor 10 ; Fibroblast Growth Factor 10 - genetics ; Fibroblast Growth Factor 10 - metabolism ; Gene Expression Regulation ; Genetics ; Gestational Age ; Humans ; Infant, Newborn ; Infant, Newborn, Diseases - genetics ; Infant, Newborn, Diseases - metabolism ; Infant, Newborn, Diseases - mortality ; Infant, Newborn, Diseases - pathology ; lacrimoauriculodentodigital (LAAD) syndrome ; Life Sciences ; Lung - embryology ; Lung - growth & development ; Lung Diseases - genetics ; Lung Diseases - metabolism ; Lung Diseases - mortality ; Lung Diseases - pathology ; lung hypoplasia ; Male ; Maternal Inheritance ; neonatal lung disease ; Organogenesis ; Paternal Inheritance ; Pedigree ; Polymorphism, Single Nucleotide - genetics ; Receptor, Fibroblast Growth Factor, Type 2 - metabolism ; Signal Transduction - genetics ; T-Box Domain Proteins - genetics ; T-Box Domain Proteins - metabolism ; T-box transcription factor 4
Is Part Of: American journal of human genetics, 2019-02, Vol.104 (2), p.213-228
Description: 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.
Publisher: United States: Elsevier Inc
Language: English
Identifier: ISSN: 0002-9297
EISSN: 1537-6605
DOI: 10.1016/j.ajhg.2018.12.010
PMID: 30639323
Source: Cell Press Free Archives
GFMER Free Medical Journals
MEDLINE
PubMed Central

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

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