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 & 52 others 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 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 journalArticle

4 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 languageEnglish (US)
Pages (from-to)213-228
Number of pages16
JournalAmerican Journal of Human Genetics
Volume104
Issue number2
DOIs
StatePublished - Feb 7 2019
Externally publishedYes

Fingerprint

Lung
Nucleotides
Organogenesis
Human Development
Morphogenesis

Keywords

  • 17q23.1q23.2 recurrent deletion
  • 5p12 deletion
  • aplasia of lacrimal and salivary glands
  • fibroblast growth factor 10
  • lacrimoauriculodentodigital (LAAD) syndrome
  • lung hypoplasia
  • neonatal lung disease
  • T-box transcription factor 4

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Karolak, J. A., Vincent, M., Deutsch, G., Gambin, T., Cogné, B., Pichon, O., ... 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

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

In: American Journal of Human Genetics, Vol. 104, No. 2, 07.02.2019, p. 213-228.

Research output: Contribution to journalArticle

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, JM, Joram, N, Bihouée, T, Scott, DA, Brown, CW, Scaglia, F, Tsai, A, 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
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 ; 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. / Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway. In: American Journal of Human Genetics. 2019 ; Vol. 104, No. 2. pp. 213-228.
@article{27cf76b0b4404c2ebabfffe4c48445ea,
title = "Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway",
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.",
keywords = "17q23.1q23.2 recurrent deletion, 5p12 deletion, aplasia of lacrimal and salivary glands, fibroblast growth factor 10, lacrimoauriculodentodigital (LAAD) syndrome, lung hypoplasia, neonatal lung disease, T-box transcription factor 4",
author = "Karolak, {Justyna A.} and Marie Vincent and Gail Deutsch and Tomasz Gambin and Benjamin Cogn{\'e} and Olivier Pichon and Francesco Vetrini and Mefford, {Heather C.} and Dines, {Jennifer N.} and Katie Golden-Grant and Katrina Dipple and Freed, {Amanda S.} and Leppig, {Kathleen A.} and Megan Dishop and David Mowat and Bruce Bennetts and Gifford, {Andrew J.} and Weber, {Martin A.} and Lee, {Anna F.} and Boerkoel, {Cornelius F.} and Bartell, {Tina M.} and Catherine Ward-Melver and Thomas Besnard and Florence Petit and Iben Bache and Zeynep T{\"u}mer and Marie Denis-Musquer and Madeleine Joubert and Jelena Martinovic and Claire B{\'e}n{\'e}teau and Arnaud Molin and Dominique Carles and Gwenaelle Andr{\'e} and Eric Bieth and Nicolas Chassaing and Louise Devisme and Lara Chalabreysse and Laurent Pasquier and V{\'e}ronique Secq and Massimiliano Don and Maria Orsaria and Chantal Missirian and J{\'e}r{\'e}mie Mortreux and Damien Sanlaville and Linda Pons and S{\'e}bastien K{\"u}ry and St{\'e}phane B{\'e}zieau and Liet, {Jean Michel} and Nicolas Joram and Tiphaine Bihou{\'e}e and Scott, {Daryl A.} and Brown, {Chester W.} and Fernando Scaglia and Anne Tsai and Grange, {Dorothy K.} and Phillips, {John A.} and Pfotenhauer, {Jean P.} and Jhangiani, {Shalini N.} and Gonzaga-Jauregui, {Claudia G.} and Chung, {Wendy K.} and Schauer, {Galen M.} and Lipson, {Mark H.} and Mercer, {Catherine L.} and {van Haeringen}, Arie and Qian Liu and Edwina Popek and {Coban Akdemir}, {Zeynep H.} and Lupski, {James R.} and Przemyslaw Szafranski and Bertrand Isidor and {Le Caignec}, Cedric and Paweł Stankiewicz",
year = "2019",
month = "2",
day = "7",
doi = "10.1016/j.ajhg.2018.12.010",
language = "English (US)",
volume = "104",
pages = "213--228",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "2",

}

TY - JOUR

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

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.

KW - 17q23.1q23.2 recurrent deletion

KW - 5p12 deletion

KW - aplasia of lacrimal and salivary glands

KW - fibroblast growth factor 10

KW - lacrimoauriculodentodigital (LAAD) syndrome

KW - lung hypoplasia

KW - neonatal lung disease

KW - T-box transcription factor 4

UR - http://www.scopus.com/inward/record.url?scp=85061000672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061000672&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2018.12.010

DO - 10.1016/j.ajhg.2018.12.010

M3 - Article

VL - 104

SP - 213

EP - 228

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 2

ER -