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 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 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

22 Citations (Scopus)

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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
Number of pages	22
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-022-34349-8
Publication status	Published - 2022

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Publisher Copyright:
© 2022, The Author(s).

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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., 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, [6664]. https://doi.org/10.1038/s41467-022-34349-8

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. / Grange, Laura J.; Reynolds, John J.; Ullah, Farid; Isidor, Bertrand; Shearer, Robert F.; Latypova, Xenia; Baxley, Ryan M.; Oliver, Antony W.; Ganesh, Anil; Cooke, Sophie L.; Jhujh, Satpal S.; McNee, Gavin S.; Hollingworth, Robert; Higgs, Martin R.; Natsume, Toyoaki; Khan, Tahir; Martos-Moreno, Gabriel; Chupp, Sharon; Mathew, Christopher G.; Parry, David; Simpson, Michael A.; Nahavandi, Nahid; Yüksel, Zafer; Drasdo, Mojgan; Kron, Anja; Vogt, Petra; Jonasson, Annemarie; Seth, Saad Ahmed; Gonzaga-Jauregui, Claudia; Brigatti, Karlla W.; Stegmann, Alexander P.A.; Kanemaki, Masato; Josifova, Dragana; Uchiyama, Yuri; Oh, Yukiko; Morimoto, Akira; Osaka, Hitoshi; Ammous, Zineb; Argente, Jesús; Matsumoto, Naomichi; Stumpel, Constance T.R.M.; Taylor, Alexander M.R.; Jackson, Andrew P.; Bielinsky, Anja Katrin; Mailand, Niels; Le Caignec, Cedric; Davis, Erica E.; Stewart, Grant S.

In: Nature Communications, Vol. 13, 6664, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

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, G, 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, AK, 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, 6664. https://doi.org/10.1038/s41467-022-34349-8

Grange, Laura J. ; Reynolds, John J. ; Ullah, Farid ; Isidor, Bertrand ; Shearer, Robert F. ; Latypova, Xenia ; Baxley, Ryan M. ; Oliver, Antony W. ; Ganesh, Anil ; Cooke, Sophie L. ; Jhujh, Satpal S. ; McNee, Gavin S. ; Hollingworth, Robert ; Higgs, Martin R. ; Natsume, Toyoaki ; Khan, Tahir ; Martos-Moreno, Gabriel ; Chupp, Sharon ; Mathew, Christopher G. ; Parry, David ; Simpson, Michael A. ; Nahavandi, Nahid ; Yüksel, Zafer ; Drasdo, Mojgan ; Kron, Anja ; Vogt, Petra ; Jonasson, Annemarie ; Seth, Saad Ahmed ; Gonzaga-Jauregui, Claudia ; Brigatti, Karlla W. ; Stegmann, Alexander P.A. ; Kanemaki, Masato ; Josifova, Dragana ; Uchiyama, Yuri ; Oh, Yukiko ; Morimoto, Akira ; Osaka, Hitoshi ; Ammous, Zineb ; Argente, Jesús ; Matsumoto, Naomichi ; Stumpel, Constance T.R.M. ; Taylor, Alexander M.R. ; Jackson, Andrew P. ; Bielinsky, Anja Katrin ; Mailand, Niels ; Le Caignec, Cedric ; Davis, Erica E. ; Stewart, Grant S. / Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy. In: Nature Communications. 2022 ; Vol. 13.

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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 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.",

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 Gabriel Martos-Moreno 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 Bielinsky, {Anja Katrin} and Niels Mailand and {Le Caignec}, Cedric and Davis, {Erica E.} and Stewart, {Grant S.}",

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doi = "10.1038/s41467-022-34349-8",

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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

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

Y1 - 2022

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.

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DO - 10.1038/s41467-022-34349-8

M3 - Journal article

C2 - 36333305

AN - SCOPUS:85141158594

VL - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 6664

ER -