Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

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

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.