Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Laura J Grange; John J Reynolds; Farid Ullah; Bertrand Isidor; Robert F Shearer; Xenia Latypova; Ryan M Baxley; Antony W Oliver; Anil Ganesh; Sophie L Cooke; Satpal S Jhujh; Gavin S McNee; Robert Hollingworth; Martin R Higgs; Toyoaki Natsume; Tahir Khan; Gabriel Á Martos-Moreno; Sharon Chupp; Christopher G Mathew; David Parry; Michael A Simpson; Nahid Nahavandi; Zafer Yüksel; Mojgan Drasdo; Anja Kron; Petra Vogt; Annemarie Jonasson; Saad Ahmed Seth; Claudia Gonzaga-Jauregui; Karlla W Brigatti; Alexander P A Stegmann; Masato Kanemaki; Dragana Josifova; Yuri Uchiyama; Yukiko Oh; Akira Morimoto; Hitoshi Osaka; Zineb Ammous; Jesús Argente; Naomichi Matsumoto; Constance T R M Stumpel; Alexander M R Taylor; Andrew P Jackson; Anja-Katrin Bielinsky; Niels Mailand; Cedric Le Caignec; Erica E Davis; Grant S Stewart

doi:10.1038/s41467-022-34349-8

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Laura J Grange, John J Reynolds, Farid Ullah, Bertrand Isidor, Robert F Shearer, Xenia Latypova, Ryan M Baxley, Antony W Oliver, Anil Ganesh, Sophie L Cooke, Satpal S Jhujh, Gavin S McNee, Robert Hollingworth, Martin R Higgs, Toyoaki Natsume, Tahir Khan, Gabriel Á Martos-Moreno, Sharon Chupp, Christopher G Mathew, David ParryMichael A Simpson, Nahid Nahavandi, Zafer Yüksel, Mojgan Drasdo, Anja Kron, Petra Vogt, Annemarie Jonasson, Saad Ahmed Seth, Claudia Gonzaga-Jauregui, Karlla W Brigatti, Alexander P A Stegmann, Masato Kanemaki, Dragana Josifova, Yuri Uchiyama, Yukiko Oh, Akira Morimoto, Hitoshi Osaka, Zineb Ammous, Jesús Argente, Naomichi Matsumoto, Constance T R M Stumpel, Alexander M R Taylor, Andrew P Jackson, Anja-Katrin Bielinsky, Niels Mailand, Cedric Le Caignec, Erica E Davis, Grant S Stewart

Cancer and Genomic Sciences

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Abstract

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

Original language	English
Article number	6664
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34349-8
Publication status	Published - 4 Nov 2022

Bibliographical note

Keywords

Humans
Cell Cycle Proteins/genetics
Microcephaly/genetics
DNA Repair/genetics
Chromosomes/metabolism
Genomic Instability
DNA-Binding Proteins/metabolism
Ubiquitin-Protein Ligases/metabolism
Chromosomal Proteins, Non-Histone/metabolism

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10.1038/s41467-022-34349-8Licence: Creative Commons: Attribution (CC BY)

GrangeLJ2022PathogenicFinal published version, 3.46 MBLicence: Creative Commons: Attribution (CC BY)

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer
Stewart, G. (Principal Investigator)
Cancer Research Uk
1/09/17 → 31/05/25
Project: Research
Cancer Research UK Birmingham Centre. See Also RCPV20624
Kearns, P. (Co-Investigator), Willcox, B. (Principal Investigator), Lee, S. (Co-Investigator), Middleton, G. (Co-Investigator), Moss, P. (Co-Investigator) & Morton, D. (Co-Investigator)
Cancer Research Uk
1/04/17 → 31/12/24
Project: Research

Cite this

Grange, L. J., Reynolds, J. J., Ullah, F., Isidor, B., Shearer, R. F., Latypova, X., Baxley, R. M., Oliver, A. W., Ganesh, A., Cooke, S. L., Jhujh, S. S., McNee, G. S., Hollingworth, R., Higgs, M. R., Natsume, T., Khan, T., Martos-Moreno, G. Á., Chupp, S., Mathew, C. G., ... Stewart, G. S. (2022). Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. Nature Communications, 13(1), Article 6664. https://doi.org/10.1038/s41467-022-34349-8

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title = "Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy",

abstract = "Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atel{\'i}s (meaning - incomplete) Syndrome. Analysis of Atel{\'i}s Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.",

keywords = "Humans, Cell Cycle Proteins/genetics, Microcephaly/genetics, DNA Repair/genetics, Chromosomes/metabolism, Genomic Instability, DNA-Binding Proteins/metabolism, Ubiquitin-Protein Ligases/metabolism, Chromosomal Proteins, Non-Histone/metabolism",

author = "Grange, {Laura J} and Reynolds, {John J} and Farid Ullah and Bertrand Isidor and Shearer, {Robert F} and Xenia Latypova and Baxley, {Ryan M} and Oliver, {Antony W} and Anil Ganesh and Cooke, {Sophie L} and Jhujh, {Satpal S} and McNee, {Gavin S} and Robert Hollingworth and Higgs, {Martin R} and Toyoaki Natsume and Tahir Khan and Martos-Moreno, {Gabriel {\'A}} and Sharon Chupp and Mathew, {Christopher G} and David Parry and Simpson, {Michael A} and Nahid Nahavandi and Zafer Y{\"u}ksel and Mojgan Drasdo and Anja Kron and Petra Vogt and Annemarie Jonasson and Seth, {Saad Ahmed} and Claudia Gonzaga-Jauregui and Brigatti, {Karlla W} and Stegmann, {Alexander P A} and Masato Kanemaki and Dragana Josifova and Yuri Uchiyama and Yukiko Oh and Akira Morimoto and Hitoshi Osaka and Zineb Ammous and Jes{\'u}s Argente and Naomichi Matsumoto and Stumpel, {Constance T R M} and Taylor, {Alexander M R} and Jackson, {Andrew P} and Anja-Katrin Bielinsky and Niels Mailand and {Le Caignec}, Cedric and Davis, {Erica E} and Stewart, {Grant S}",

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Grange, LJ, Reynolds, JJ, Ullah, F, Isidor, B, Shearer, RF, Latypova, X, Baxley, RM, Oliver, AW, Ganesh, A, Cooke, SL, Jhujh, SS , McNee, GS, Hollingworth, R, Higgs, MR, Natsume, T, Khan, T, Martos-Moreno, GÁ, Chupp, S, Mathew, CG, Parry, D, Simpson, MA, Nahavandi, N, Yüksel, Z, Drasdo, M, Kron, A, Vogt, P, Jonasson, A, Seth, SA, Gonzaga-Jauregui, C, Brigatti, KW, Stegmann, APA, Kanemaki, M, Josifova, D, Uchiyama, Y, Oh, Y, Morimoto, A, Osaka, H, Ammous, Z, Argente, J, Matsumoto, N, Stumpel, CTRM, Taylor, AMR, Jackson, AP, Bielinsky, A-K, Mailand, N, Le Caignec, C, Davis, EE & Stewart, GS 2022, 'Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy', Nature Communications, vol. 13, no. 1, 6664. https://doi.org/10.1038/s41467-022-34349-8

TY - JOUR

T1 - Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

AU - Grange, Laura J

AU - Reynolds, John J

AU - Ullah, Farid

AU - Isidor, Bertrand

AU - Shearer, Robert F

AU - Latypova, Xenia

AU - Baxley, Ryan M

AU - Oliver, Antony W

AU - Ganesh, Anil

AU - Cooke, Sophie L

AU - Jhujh, Satpal S

AU - McNee, Gavin S

AU - Hollingworth, Robert

AU - Higgs, Martin R

AU - Natsume, Toyoaki

AU - Khan, Tahir

AU - Martos-Moreno, Gabriel Á

AU - Chupp, Sharon

AU - Mathew, Christopher G

AU - Parry, David

AU - Simpson, Michael A

AU - Nahavandi, Nahid

AU - Yüksel, Zafer

AU - Drasdo, Mojgan

AU - Kron, Anja

AU - Vogt, Petra

AU - Jonasson, Annemarie

AU - Seth, Saad Ahmed

AU - Gonzaga-Jauregui, Claudia

AU - Brigatti, Karlla W

AU - Stegmann, Alexander P A

AU - Kanemaki, Masato

AU - Josifova, Dragana

AU - Uchiyama, Yuri

AU - Oh, Yukiko

AU - Morimoto, Akira

AU - Osaka, Hitoshi

AU - Ammous, Zineb

AU - Argente, Jesús

AU - Matsumoto, Naomichi

AU - Stumpel, Constance T R M

AU - Taylor, Alexander M R

AU - Jackson, Andrew P

AU - Bielinsky, Anja-Katrin

AU - Mailand, Niels

AU - Le Caignec, Cedric

AU - Davis, Erica E

AU - Stewart, Grant S

PY - 2022/11/4

Y1 - 2022/11/4

N2 - Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

AB - Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.

KW - Humans

KW - Cell Cycle Proteins/genetics

KW - Microcephaly/genetics

KW - DNA Repair/genetics

KW - Chromosomes/metabolism

KW - Genomic Instability

KW - DNA-Binding Proteins/metabolism

KW - Ubiquitin-Protein Ligases/metabolism

KW - Chromosomal Proteins, Non-Histone/metabolism

U2 - 10.1038/s41467-022-34349-8

DO - 10.1038/s41467-022-34349-8

M3 - Article

C2 - 36333305

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6664

ER -

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Projects

Characterising novel regulators of the PI-3-kinase-like kinase-dependent DNA damage response and their role in preventing human disease and cancer

Cancer Research UK Birmingham Centre. See Also RCPV20624

Cite this