dc.contributor.author
Melo, Uirá Souto
dc.contributor.author
Piard, Juliette
dc.contributor.author
Fischer-Zirnsak, Björn
dc.contributor.author
Klever, Marius-Konstantin
dc.contributor.author
Schöpflin, Robert
dc.contributor.author
Mensah, Martin Atta
dc.contributor.author
Holtgrewe, Manuel
dc.contributor.author
Arbez-Gindre, Francine
dc.contributor.author
Martin, Alain
dc.contributor.author
Guigue, Virginie
dc.contributor.author
Gaillard, Dominique
dc.contributor.author
Landais, Emilie
dc.contributor.author
Roze, Virginie
dc.contributor.author
Kremer, Valerie
dc.contributor.author
Ramanah, Rajeev
dc.contributor.author
Cabrol, Christelle
dc.contributor.author
Harms, Frederike L.
dc.contributor.author
Kornak, Uwe
dc.contributor.author
Spielmann, Malte
dc.contributor.author
Mundlos, Stefan
dc.contributor.author
Maldergem, Lionel Van
dc.date.accessioned
2023-08-11T14:38:18Z
dc.date.available
2023-08-11T14:38:18Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/40481
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-40202
dc.description.abstract
During human organogenesis, lung development is a timely and tightly regulated developmental process under the control of a large number of signaling molecules. Understanding how genetic variants can disturb normal lung development causing different lung malformations is a major goal for dissecting molecular mechanisms during embryogenesis. Here, through exome sequencing (ES), array CGH, genome sequencing (GS) and Hi-C, we aimed at elucidating the molecular basis of bilateral isolated lung agenesis in three fetuses born to a non-consanguineous family. We detected a complex genomic rearrangement containing duplicated, triplicated and deleted fragments involving the SHH locus in fetuses presenting complete agenesis of both lungs and near-complete agenesis of the trachea, diagnosed by ultrasound screening and confirmed at autopsy following termination. The rearrangement did not include SHH itself, but several regulatory elements for lung development, such as MACS1, a major SHH lung enhancer, and the neighboring genes MNX1 and NOM1. The rearrangement incorporated parts of two topologically associating domains (TADs) including their boundaries. Hi-C of cells from one of the affected fetuses showed the formation of two novel TADs each containing SHH enhancers and the MNX1 and NOM1 genes. Hi-C together with GS indicate that the new 3D conformation is likely causative for this condition by an inappropriate activation of MNX1 included in the neo-TADs by MACS1 enhancer, further highlighting the importance of the 3D chromatin conformation in human disease.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
Complete lung agenesis
en
dc.subject
complex genomic rearrangement
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.doi
10.1007/s00439-021-02344-6
dcterms.bibliographicCitation.journaltitle
Human Genetics
dcterms.bibliographicCitation.number
10
dcterms.bibliographicCitation.originalpublishername
Springer Nature
dcterms.bibliographicCitation.pagestart
1459
dcterms.bibliographicCitation.pageend
1469
dcterms.bibliographicCitation.volume
140
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.funding
Springer Nature DEAL
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
34436670
dcterms.isPartOf.issn
0340-6717
dcterms.isPartOf.eissn
1432-1203