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  Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus

Melo, U. S., Piard, J., Fischer-Zirnsak, B., Klever, M.-K., Schöpflin, R., Atta Mensah, M., et al. (2021). Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus. Human Genetics, 140, 1459-1469. doi:10.1007/s00439-021-02344-6.

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Melo, Uirá Souto1, Author              
Piard, Juliette , Author
Fischer-Zirnsak, Björn , Author
Klever, Marius-Konstantin1, Author              
Schöpflin, Robert1, Author              
Atta Mensah, Martin , Author
Holtgrewe, Manuel , Author
Arbez-Gindre, Francine , Author
Martin, Alain, Author
Guigue, Virginie , Author
Gaillard, Dominique , Author
Landais, Emilie , Author
Roze, Virginie , Author
Kremer, Valerie , Author
Ramanah, Rajeev , Author
Cabrol, Christelle , Author
Harms, Frederike L. , Author
Kornak, Uwe, Author
Spielmann, Malte2, Author              
Mundlos, Stefan1, Author              
Van Maldergem, Lionel , Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014183              

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 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.

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Language(s): eng - English
 Dates: 2021-08-102021-08-262021-10
 Publication Status: Published in print
 Pages: -
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 Rev. Type: -
 Identifiers: DOI: 10.1007/s00439-021-02344-6
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Title: Human Genetics
Source Genre: Journal
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Publ. Info: Berlin : Springer-Verlag
Pages: 11 Volume / Issue: 140 Sequence Number: - Start / End Page: 1459 - 1469 Identifier: ISSN: 0340-6717
CoNE: https://pure.mpg.de/cone/journals/resource/954925519623