Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

TitlePathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.
Publication TypeJournal Article
Year of Publication2016
AuthorsSzafranski, P, Gambin, T, Dharmadhikari, AV, Akdemir, KCaner, Jhangiani, SN, Schuette, J, Godiwala, N, Yatsenko, SA, Sebastian, J, Madan-Khetarpal, S, Surti, U, Abellar, RG, Bateman, DA, Wilson, AL, Markham, MH, Slamon, J, Santos-Simarro, F, Palomares, M, Nevado, J, Lapunzina, P, Chung, BHon-Yin, Wong, W-L, Chu, YWing Yiu, Mok, GTsz Kin, Kerem, E, Reiter, J, Ambalavanan, N, Anderson, SA, Kelly, DR, Shieh, J, Rosenthal, TC, Scheible, K, Steiner, L, M Iqbal, A, McKinnon, ML, Hamilton, SJane, Schlade-Bartusiak, K, English, D, Hendson, G, Roeder, ER, DeNapoli, TS, Littlejohn, ROkashah, Wolff, DJ, Wagner, CL, Yeung, A, Francis, D, Fiorino, EK, Edelman, M, Fox, J, Hayes, DA, Janssens, S, De Baere, E, Menten, B, Loccufier, A, Vanwalleghem, L, Moerman, P, Sznajer, Y, Lay, AS, Kussmann, JL, Chawla, J, Payton, DJ, Phillips, GE, Brosens, E, Tibboel, D, de Klein, A, Maystadt, I, Fisher, R, Sebire, N, Male, A, Chopra, M, Pinner, J, Malcolm, G, Peters, G, Arbuckle, S, Lees, M, Mead, Z, Quarrell, O, Sayers, R, Owens, M, Shaw-Smith, C, Lioy, J, McKay, E, de Leeuw, N, Feenstra, I, Spruijt, L, Elmslie, F, Thiruchelvam, T, Bacino, CA, Langston, C, Lupski, JR, Sen, P, Popek, E, Stankiewicz, P
JournalHum Genet
Volume135
Issue5
Pagination569-586
Date Published2016 May
ISSN1432-1203
KeywordsChromosomes, Human, Pair 16, Comparative Genomic Hybridization, Female, Forkhead Transcription Factors, Genes, Lethal, Genome, Human, Genomic Imprinting, High-Throughput Nucleotide Sequencing, Humans, Infant, Newborn, Male, Pedigree, Persistent Fetal Circulation Syndrome, Pulmonary Alveoli, Pulmonary Veins, Sequence Deletion
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.

DOI10.1007/s00439-016-1655-9
Alternate JournalHum Genet
PubMed ID27071622
PubMed Central IDPMC5518754
Grant ListR01HL101975 / HL / NHLBI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States
R01 HL101975 / HL / NHLBI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
HG006542 / HG / NHGRI NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
NS058529 / NS / NINDS NIH HHS / United States

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