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 Boerkoel; Tina 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

doi:10.1016/j.ajhg.2018.12.010

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

Medical Genetics Program

33 Citations (Scopus)

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 ∼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 language	English
Journal	American Journal of Human Genetics
Volume	104
Issue number	2
Pages (from-to)	213-228
Number of pages	16
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2018.12.010
Publication status	Published - 7 Feb 2019

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10.1016/j.ajhg.2018.12.010

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Karolak, J. A., Vincent, M., Deutsch, G., Gambin, T., Cogné, B., Pichon, O., Vetrini, F., Mefford, H. C., Dines, J. N., Golden-Grant, K., Dipple, K., Freed, A. S., Leppig, K. A., Dishop, M., Mowat, D., Bennetts, B., Gifford, A. J., Weber, M. A., Lee, A. F., ... Stankiewicz, P. (2019). Complex Compound Inheritance of Lethal Lung Developmental Disorders due to Disruption of the TBX-FGF Pathway. American Journal of Human Genetics, 104(2), 213-228. https://doi.org/10.1016/j.ajhg.2018.12.010

Karolak, JA, Vincent, M, Deutsch, G, Gambin, T, Cogné, B, Pichon, O, Vetrini, F, Mefford, HC, Dines, JN, Golden-Grant, K, Dipple, K, Freed, AS, Leppig, KA, Dishop, M, Mowat, D, Bennetts, B, Gifford, AJ, Weber, MA, Lee, AF, Boerkoel, CF, Bartell, TM, Ward-Melver, C, Besnard, T, Petit, F, Bache, I , Tümer, Z, Denis-Musquer, M, Joubert, M, Martinovic, J, Bénéteau, C, Molin, A, Carles, D, André, G, Bieth, E, Chassaing, N, Devisme, L, Chalabreysse, L, Pasquier, L, Secq, V, Don, M, Orsaria, M, Missirian, C, Mortreux, J, Sanlaville, D, Pons, L, Küry, S, Bézieau, S, Liet, J-M, Joram, N, Bihouée, T, Scott, DA, Brown, CW, Scaglia, F, Tsai, AC-H, Grange, DK, Phillips, JA, Pfotenhauer, JP, Jhangiani, SN, Gonzaga-Jauregui, CG, Chung, WK, Schauer, GM, Lipson, MH, Mercer, CL, van Haeringen, A, Liu, Q, Popek, E, Coban Akdemir, ZH, Lupski, JR, Szafranski, P, Isidor, B, Le Caignec, C & Stankiewicz, P 2019, 'Complex Compound Inheritance of Lethal Lung Developmental Disorders due to Disruption of the TBX-FGF Pathway', American Journal of Human Genetics, vol. 104, no. 2, pp. 213-228. https://doi.org/10.1016/j.ajhg.2018.12.010

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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 ∼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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doi = "10.1016/j.ajhg.2018.12.010",

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T1 - Complex Compound Inheritance of Lethal Lung Developmental Disorders due to Disruption of the TBX-FGF Pathway

AU - Karolak, Justyna A

AU - Vincent, Marie

AU - Deutsch, Gail

AU - Gambin, Tomasz

AU - Cogné, Benjamin

AU - Pichon, Olivier

AU - Vetrini, Francesco

AU - Mefford, Heather C

AU - Dines, Jennifer N

AU - Golden-Grant, Katie

AU - Dipple, Katrina

AU - Freed, Amanda S

AU - Leppig, Kathleen A

AU - Dishop, Megan

AU - Mowat, David

AU - Bennetts, Bruce

AU - Gifford, Andrew J

AU - Weber, Martin A

AU - Lee, Anna F

AU - Boerkoel, Cornelius F

AU - Bartell, Tina M

AU - Ward-Melver, Catherine

AU - Besnard, Thomas

AU - Petit, Florence

AU - Bache, Iben

AU - Tümer, Zeynep

AU - Denis-Musquer, Marie

AU - Joubert, Madeleine

AU - Martinovic, Jelena

AU - Bénéteau, Claire

AU - Molin, Arnaud

AU - Carles, Dominique

AU - André, Gwenaelle

AU - Bieth, Eric

AU - Chassaing, Nicolas

AU - Devisme, Louise

AU - Chalabreysse, Lara

AU - Pasquier, Laurent

AU - Secq, Véronique

AU - Don, Massimiliano

AU - Orsaria, Maria

AU - Missirian, Chantal

AU - Mortreux, Jérémie

AU - Sanlaville, Damien

AU - Pons, Linda

AU - Küry, Sébastien

AU - Bézieau, Stéphane

AU - Liet, Jean-Michel

AU - Joram, Nicolas

AU - Bihouée, Tiphaine

AU - Scott, Daryl A

AU - Brown, Chester W

AU - Scaglia, Fernando

AU - Tsai, Anne Chun-Hui

AU - Grange, Dorothy K

AU - Phillips, John A

AU - Pfotenhauer, Jean P

AU - Jhangiani, Shalini N

AU - Gonzaga-Jauregui, Claudia G

AU - Chung, Wendy K

AU - Schauer, Galen M

AU - Lipson, Mark H

AU - Mercer, Catherine L

AU - van Haeringen, Arie

AU - Liu, Qian

AU - Popek, Edwina

AU - Coban Akdemir, Zeynep H

AU - Lupski, James R

AU - Szafranski, Przemyslaw

AU - Isidor, Bertrand

AU - Le Caignec, Cedric

AU - Stankiewicz, Paweł

PY - 2019/2/7

Y1 - 2019/2/7

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2018.12.010

DO - 10.1016/j.ajhg.2018.12.010

M3 - Journal article

C2 - 30639323

SN - 0002-9297

VL - 104

SP - 213

EP - 228

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 2

ER -

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

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