Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

Szafranski, Przemyslaw, Gambin, Tomasz, Dharmadhikari, Avinash V., Akdemir, Kadir Caner, Jhangiani, Shalini N., Schuette, Jennifer, Godiwala, Nihal, Yatsenko, Svetlana A., Sebastian, Jessica, Madan-Khetarpal, Suneeta, Surti, Urvashi, Abellar, Rosanna G., Bateman, David A., Wilson, Ashley L., Markham, Melinda H., Slamon, Jill, Santos-Simarro, Fernando, Palomares, Maria, Nevado, Julian, Lapunzina, Pablo, Chung, Brian Hon-Yin, Wong, Wai-Lap, Chu, Yoyo Wing Yiu, Mok, Gary Tsz Kin, Kerem, Eitan, Reiter, Joel, Ambalavanan, Namasivayam, Anderson, Scott A., Kelly, David R., Shieh, Joseph, Rosenthal, Taryn C., Scheible, Kristin, Steiner, Laurie, Iqbal, M. Anwar, McKinnon, Margaret L., Hamilton, Sara Jane, Schlade-Bartusiak, Kamilla, English, Dawn, Hendson, Glenda, Roeder, Elizabeth R., DeNapoli, Thomas S., Littlejohn, Rebecca Okashah, Wolff, Daynna J., Wagner, Carol L., Yeung, Alison, Francis, David, Fiorino, Elizabeth K., Edelman, Morris, Fox, Joyce, Hayes, Denise A., Janssens, Sandra, de Baere, Elfride, Menten, Bjorn, Loccufier, Anne, Vanwalleghem, Lieve, Moerman, Philippe, Sznajer, Yves, Lay, Amy S., Kussmann, Jennifer L., Chawla, Jasneek, Payton, Diane J., Phillips, Gael E., Brosens, Erwin, Tibboel, Dick, de Klein, Annelies, Maystadt, Isbelle, Fisher, Richard, Sebire, Neil, Male, Alison, Chopra, Maya, Pinner, Jason, Malcolm, Girvan, Peters, Gregory, Arbuckle, Susan, Lees, Melissa, Mead, Zoe, Quarrell, Oliver, Sayers, Richard, Owens, Martina, Shaw-Smith, Charles, Lioy, Janet, McKay, Eileen, de Leeuw, Nicole, Feenstra, Ilse, Spruijt, Liesbeth, Elmslie, Frances, Thiruchelvam, Timothy, Bacino, Carlos A., Langston, Claire, Lupski, James R., Sen, Partha, Popek, Edwina and Stankiewicz, Pawel (2016) Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. Human Genetics, 135 5: 569-586. doi:10.1007/s00439-016-1655-9


Author Szafranski, Przemyslaw
Gambin, Tomasz
Dharmadhikari, Avinash V.
Akdemir, Kadir Caner
Jhangiani, Shalini N.
Schuette, Jennifer
Godiwala, Nihal
Yatsenko, Svetlana A.
Sebastian, Jessica
Madan-Khetarpal, Suneeta
Surti, Urvashi
Abellar, Rosanna G.
Bateman, David A.
Wilson, Ashley L.
Markham, Melinda H.
Slamon, Jill
Santos-Simarro, Fernando
Palomares, Maria
Nevado, Julian
Lapunzina, Pablo
Chung, Brian Hon-Yin
Wong, Wai-Lap
Chu, Yoyo Wing Yiu
Mok, Gary Tsz Kin
Kerem, Eitan
Reiter, Joel
Ambalavanan, Namasivayam
Anderson, Scott A.
Kelly, David R.
Shieh, Joseph
Rosenthal, Taryn C.
Scheible, Kristin
Steiner, Laurie
Iqbal, M. Anwar
McKinnon, Margaret L.
Hamilton, Sara Jane
Schlade-Bartusiak, Kamilla
English, Dawn
Hendson, Glenda
Roeder, Elizabeth R.
DeNapoli, Thomas S.
Littlejohn, Rebecca Okashah
Wolff, Daynna J.
Wagner, Carol L.
Yeung, Alison
Francis, David
Fiorino, Elizabeth K.
Edelman, Morris
Fox, Joyce
Hayes, Denise A.
Janssens, Sandra
de Baere, Elfride
Menten, Bjorn
Loccufier, Anne
Vanwalleghem, Lieve
Moerman, Philippe
Sznajer, Yves
Lay, Amy S.
Kussmann, Jennifer L.
Chawla, Jasneek
Payton, Diane J.
Phillips, Gael E.
Brosens, Erwin
Tibboel, Dick
de Klein, Annelies
Maystadt, Isbelle
Fisher, Richard
Sebire, Neil
Male, Alison
Chopra, Maya
Pinner, Jason
Malcolm, Girvan
Peters, Gregory
Arbuckle, Susan
Lees, Melissa
Mead, Zoe
Quarrell, Oliver
Sayers, Richard
Owens, Martina
Shaw-Smith, Charles
Lioy, Janet
McKay, Eileen
de Leeuw, Nicole
Feenstra, Ilse
Spruijt, Liesbeth
Elmslie, Frances
Thiruchelvam, Timothy
Bacino, Carlos A.
Langston, Claire
Lupski, James R.
Sen, Partha
Popek, Edwina
Stankiewicz, Pawel
Title Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins
Journal name Human Genetics   Check publisher's open access policy
ISSN 1432-1203
0340-6717
Publication date 2016-05
Year available 2016
Sub-type Article (original research)
DOI 10.1007/s00439-016-1655-9
Open Access Status Not yet assessed
Volume 135
Issue 5
Start page 569
End page 586
Total pages 18
Place of publication Heidelberg, Germany
Publisher Springer
Collection year 2017
Language eng
Formatted abstract
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.
Keyword Alveolar capillary dysplasia with misalignment of pulmonary veins
(ACDMPV)
Lung developmental disorder
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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