PortalPublikationenComplete lung agenesis caused by complex genomic rearrangeme...

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

Standard

Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus. / Melo, Uirá Souto; Piard, Juliette; Fischer-Zirnsak, Björn; Klever, Marius-Konstantin; Schöpflin, Robert; Mensah, Martin Atta; Holtgrewe, Manuel; Arbez-Gindre, Francine; Martin, Alain; Guigue, Virginie; Gaillard, Dominique; Landais, Emilie; Roze, Virginie; Kremer, Valerie; Ramanah, Rajeev; Cabrol, Christelle; Harms, Frederike L; Kornak, Uwe; Spielmann, Malte; Mundlos, Stefan; Van Maldergem, Lionel.

in: HUM GENET, Jahrgang 140, Nr. 10, 10.2021, S. 1459-1469.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Melo, US, Piard, J, Fischer-Zirnsak, B, Klever, M-K, Schöpflin, R, Mensah, MA, Holtgrewe, M, Arbez-Gindre, F, Martin, A, Guigue, V, Gaillard, D, Landais, E, Roze, V, Kremer, V, Ramanah, R, Cabrol, C, Harms, FL, Kornak, U, Spielmann, M, Mundlos, S & Van Maldergem, L 2021, 'Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus', HUM GENET, Jg. 140, Nr. 10, S. 1459-1469. https://doi.org/10.1007/s00439-021-02344-6

APA

Melo, U. S., Piard, J., Fischer-Zirnsak, B., Klever, M-K., Schöpflin, R., Mensah, M. A., Holtgrewe, M., Arbez-Gindre, F., Martin, A., Guigue, V., Gaillard, D., Landais, E., Roze, V., Kremer, V., Ramanah, R., Cabrol, C., Harms, F. L., Kornak, U., Spielmann, M., ... Van Maldergem, L. (2021). Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus. HUM GENET, 140(10), 1459-1469. https://doi.org/10.1007/s00439-021-02344-6

Vancouver

Melo US, Piard J, Fischer-Zirnsak B, Klever M-K, Schöpflin R, Mensah MA et al. Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus. HUM GENET. 2021 Okt;140(10):1459-1469. https://doi.org/10.1007/s00439-021-02344-6

Bibtex

@article{3d7711555a424e38b632c955a233095a,
title = "Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus",
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.",
keywords = "Abnormalities, Multiple/genetics, Adult, Cadaver, Evolution, Molecular, Female, Fetus, Genetic Variation, Genome, Human, Humans, Lung/abnormalities, Lung Diseases/genetics, Male, Organogenesis/genetics, Pregnancy",
author = "Melo, {Uir{\'a} Souto} and Juliette Piard and Bj{\"o}rn Fischer-Zirnsak and Marius-Konstantin Klever and Robert Sch{\"o}pflin and Mensah, {Martin Atta} and Manuel Holtgrewe and Francine Arbez-Gindre and Alain Martin and Virginie Guigue and Dominique Gaillard and Emilie Landais and Virginie Roze and Valerie Kremer and Rajeev Ramanah and Christelle Cabrol and Harms, {Frederike L} and Uwe Kornak and Malte Spielmann and Stefan Mundlos and {Van Maldergem}, Lionel",
note = "{\textcopyright} 2021. The Author(s).",
year = "2021",
month = oct,
doi = "10.1007/s00439-021-02344-6",
language = "English",
volume = "140",
pages = "1459--1469",
journal = "HUM GENET",
issn = "0340-6717",
publisher = "Springer",
number = "10",

}

RIS

TY - JOUR

T1 - Complete lung agenesis caused by complex genomic rearrangements with neo-TAD formation at the SHH locus

AU - Melo, Uirá Souto

AU - Piard, Juliette

AU - Fischer-Zirnsak, Björn

AU - Klever, Marius-Konstantin

AU - Schöpflin, Robert

AU - Mensah, Martin Atta

AU - Holtgrewe, Manuel

AU - Arbez-Gindre, Francine

AU - Martin, Alain

AU - Guigue, Virginie

AU - Gaillard, Dominique

AU - Landais, Emilie

AU - Roze, Virginie

AU - Kremer, Valerie

AU - Ramanah, Rajeev

AU - Cabrol, Christelle

AU - Harms, Frederike L

AU - Kornak, Uwe

AU - Spielmann, Malte

AU - Mundlos, Stefan

AU - Van Maldergem, Lionel

N1 - © 2021. The Author(s).

PY - 2021/10

Y1 - 2021/10

N2 - 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.

AB - 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.

KW - Abnormalities, Multiple/genetics

KW - Adult

KW - Cadaver

KW - Evolution, Molecular

KW - Female

KW - Fetus

KW - Genetic Variation

KW - Genome, Human

KW - Humans

KW - Lung/abnormalities

KW - Lung Diseases/genetics

KW - Male

KW - Organogenesis/genetics

KW - Pregnancy

U2 - 10.1007/s00439-021-02344-6

DO - 10.1007/s00439-021-02344-6

M3 - SCORING: Journal article

C2 - 34436670

VL - 140

SP - 1459

EP - 1469

JO - HUM GENET

JF - HUM GENET

SN - 0340-6717

IS - 10

ER -