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Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

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.

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Acknowledgements

We are grateful to the ACDMPV families for participation in these studies and the ACD Association for coordination of family recruitments. We thank Drs. K. Aagaard, A.L. Beaudet, J.W. Belmont, A.K. Groves, B. Lee, J.R. Neilson, S.E. Plon, I.B. van den Veyver, and H.Y. Zoghbi for helpful discussion and J.A. Rosenfeld-Mokry for critically reading the manuscript. This work was supported by grants awarded by the US National Heart, Lung, and Blood Institute (NHLBI) grant RO1HL101975 to PSt, NORD grants to PSz, US National Human Genome Research Institute (NHGRI)/NHLBI grant HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and National Institute of Neurological Disorders and Stroke (NINDS) grant NS058529 to JRL.

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Szafranski, P., Gambin, T., Dharmadhikari, A.V. et al. Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Genet 135, 569–586 (2016). https://doi.org/10.1007/s00439-016-1655-9

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Keywords

  • Hypoplastic Left Heart Syndrome
  • Whole Exome Sequencing
  • Upstream Regulatory Region
  • Paternal Chromosome
  • Maternal Chromosome