%0 Journal Article %J Am J Hum Genet %D 2019 %T Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway. %A Karolak, Justyna A %A Vincent, Marie %A Deutsch, Gail %A Gambin, Tomasz %A Cogné, Benjamin %A Pichon, Olivier %A Vetrini, Francesco %A Mefford, Heather C %A Dines, Jennifer N %A Golden-Grant, Katie %A Dipple, Katrina %A Freed, Amanda S %A Leppig, Kathleen A %A Dishop, Megan %A Mowat, David %A Bennetts, Bruce %A Gifford, Andrew J %A Weber, Martin A %A Lee, Anna F %A Boerkoel, Cornelius F %A Bartell, Tina M %A Ward-Melver, Catherine %A Besnard, Thomas %A Petit, Florence %A Bache, Iben %A Tümer, Zeynep %A Denis-Musquer, Marie %A Joubert, Madeleine %A Martinovic, Jelena %A Bénéteau, Claire %A Molin, Arnaud %A Carles, Dominique %A André, Gwenaelle %A Bieth, Eric %A Chassaing, Nicolas %A Devisme, Louise %A Chalabreysse, Lara %A Pasquier, Laurent %A Secq, Véronique %A Don, Massimiliano %A Orsaria, Maria %A Missirian, Chantal %A Mortreux, Jérémie %A Sanlaville, Damien %A Pons, Linda %A Küry, Sébastien %A Bézieau, Stéphane %A Liet, Jean-Michel %A Joram, Nicolas %A Bihouée, Tiphaine %A Scott, Daryl A %A Brown, Chester W %A Scaglia, Fernando %A Tsai, Anne Chun-Hui %A Grange, Dorothy K %A Phillips, John A %A Pfotenhauer, Jean P %A Jhangiani, Shalini N %A Gonzaga-Jauregui, Claudia G %A Chung, Wendy K %A Schauer, Galen M %A Lipson, Mark H %A Mercer, Catherine L %A van Haeringen, Arie %A Liu, Qian %A Popek, Edwina %A Coban Akdemir, Zeynep H %A James R Lupski %A Szafranski, Przemyslaw %A Isidor, Bertrand %A Le Caignec, Cedric %A Stankiewicz, Paweł %K DNA Copy Number Variations %K Female %K Fibroblast Growth Factor 10 %K Gene Expression Regulation %K Gestational Age %K Humans %K Infant, Newborn %K Infant, Newborn, Diseases %K Lung %K Lung Diseases %K Male %K Maternal Inheritance %K Organogenesis %K Paternal Inheritance %K Pedigree %K Polymorphism, Single Nucleotide %K Receptor, Fibroblast Growth Factor, Type 2 %K Signal Transduction %K T-Box Domain Proteins %X

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.

%B Am J Hum Genet %V 104 %P 213-228 %8 2019 Feb 07 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/30639323?dopt=Abstract %R 10.1016/j.ajhg.2018.12.010 %0 Journal Article %J Am J Med Genet A %D 2016 %T Phenotypic expansion of TBX4 mutations to include acinar dysplasia of the lungs. %A Szafranski, Przemyslaw %A Coban-Akdemir, Zeynep H %A Rupps, Rosemarie %A Grazioli, Serge %A Wensley, David %A Jhangiani, Shalini N %A Popek, Edwina %A Lee, Anna F %A Lupski, James R %A Boerkoel, Cornelius F %A Stankiewicz, Paweł %K Alleles %K Autopsy %K Chromosomes, Human, Pair 16 %K DNA Copy Number Variations %K DNA Mutational Analysis %K Fatal Outcome %K Female %K Genetic Association Studies %K Genotype %K Heterozygote %K Humans %K Infant, Newborn %K Karyotype %K Lung %K Mutation %K Pedigree %K Phenotype %K Radiography, Thoracic %K T-Box Domain Proteins %X

Mutations in the T-box transcription factor TBX4 gene have been reported in patients with Ischiocoxopodopatellar syndrome (MIM# 147891) and childhood-onset pulmonary arterial hypertension. Whole exome sequencing of DNA from a 1 day old deceased newborn, with severe diffuse developmental lung disorder exhibiting features of acinar dysplasia, and her unaffected parents identified a de novo TBX4 missense mutation p.E86Q (c.256G>C) in the DNA-binding T-box domain. We propose phenotypic expansion of the TBX4-related clinical disease spectrum to include acinar dysplasia of the lungs. The reported mutation is the first identified genetic variant causative for acinar dysplasia. © 2016 Wiley Periodicals, Inc.

%B Am J Med Genet A %V 170 %P 2440-4 %8 2016 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/27374786?dopt=Abstract %R 10.1002/ajmg.a.37822