Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus.
Journal
Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
received:
03
06
2021
accepted:
10
08
2021
pubmed:
27
8
2021
medline:
1
10
2021
entrez:
26
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34436670
doi: 10.1007/s00439-021-02344-6
pii: 10.1007/s00439-021-02344-6
pmc: PMC8460539
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1459-1469Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : SP1532/3-1
Organisme : Deutsche Forschungsgemeinschaft
ID : SP1532/5-1
Organisme : Deutsche Forschungsgemeinschaft
ID : MU 880/16-1
Organisme : Deutsche Forschungsgemeinschaft
ID : KU 1240/10-1
Informations de copyright
© 2021. The Author(s).
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