Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy
Laura J Grange
(1)
,
John J Reynolds
(1)
,
Farid Ullah
(2, 3, 4)
,
Bertrand Isidor
(5)
,
Robert F Shearer
(6)
,
Xenia Latypova
(5)
,
Ryan M Baxley
(7)
,
Antony W Oliver
(8)
,
Anil Ganesh
(1)
,
Sophie L Cooke
(1)
,
Satpal S Jhujh
(1)
,
Gavin S Mcnee
(1)
,
Robert Hollingworth
(1)
,
Martin R Higgs
(1)
,
Toyoaki Natsume
(9)
,
Tahir Khan
(10)
,
Gabriel Á Martos-Moreno
,
Sharon Chupp
,
Christopher G Mathew
(11)
,
David Parry
(12)
,
Michael A Simpson
(13)
,
Nahid Nahavandi
(14)
,
Zafer Yüksel
(14)
,
Mojgan Drasdo
(14)
,
Anja Kron
(14)
,
Petra Vogt
(14)
,
Annemarie Jonasson
(14)
,
Saad Ahmed Seth
,
Claudia Gonzaga-Jauregui
(15)
,
Karlla W Brigatti
,
Alexander P A Stegmann
(16, 17)
,
Masato Kanemaki
(18)
,
Dragana Josifova
(19)
,
Yuri Uchiyama
,
Yukiko Oh
(20)
,
Akira Morimoto
(20)
,
Hitoshi Osaka
(21)
,
Zineb Ammous
,
Jesús Argente
(22)
,
Naomichi Matsumoto
,
Constance T R M Stumpel
(17)
,
Alexander M R Taylor
(23)
,
Andrew P Jackson
(24)
,
Anja-Katrin Bielinsky
,
Niels Mailand
,
Cedric Le Caignec
(25, 26)
,
Erica E Davis
,
Grant S Stewart
1
University of Birmingham [Birmingham]
2 Ann & Robert H. Lurie Children's Hospital of Chicago
3 GCUF - Government College University of Faisalabad
4 PIEAS - Pakistan Institute of Engineering and Applied Sciences
5 Service de génétique médicale - Unité de génétique clinique [Nantes]
6 CPR - Novo Nordisk Foundation Center for Protein Research
7 UMN - University of Minnesota System
8 University of Sussex
9 NIG - National Institute of Genetics [Mishima, Japan]
10 Duke University Medical Center
11 WITS - University of the Witwatersrand [Johannesburg]
12 IGMM - MRC Institute of Genetics and Molecular Medicine [Edinburgh]
13 King‘s College London
14 Boehringer Ingelheim
15 UNAM - Universidad Nacional Autónoma de México = National Autonomous University of Mexico
16 Radboud University [Nijmegen]
17 MUMC - Maastricht University Medical Centre
18 Research Organization of Information and Systems
19 Division of Medical & Molecular Genetics
20 Department of Pediatrics
21 UC San Diego - University of California [San Diego]
22 HIUNJ - Hospital Infantil Universitario Niño Jesús
23 University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA]
24 Trinity College Dublin
25 Service Génétique Médicale [CHU Toulouse]
26 ToNIC - Toulouse NeuroImaging Center
2 Ann & Robert H. Lurie Children's Hospital of Chicago
3 GCUF - Government College University of Faisalabad
4 PIEAS - Pakistan Institute of Engineering and Applied Sciences
5 Service de génétique médicale - Unité de génétique clinique [Nantes]
6 CPR - Novo Nordisk Foundation Center for Protein Research
7 UMN - University of Minnesota System
8 University of Sussex
9 NIG - National Institute of Genetics [Mishima, Japan]
10 Duke University Medical Center
11 WITS - University of the Witwatersrand [Johannesburg]
12 IGMM - MRC Institute of Genetics and Molecular Medicine [Edinburgh]
13 King‘s College London
14 Boehringer Ingelheim
15 UNAM - Universidad Nacional Autónoma de México = National Autonomous University of Mexico
16 Radboud University [Nijmegen]
17 MUMC - Maastricht University Medical Centre
18 Research Organization of Information and Systems
19 Division of Medical & Molecular Genetics
20 Department of Pediatrics
21 UC San Diego - University of California [San Diego]
22 HIUNJ - Hospital Infantil Universitario Niño Jesús
23 University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA]
24 Trinity College Dublin
25 Service Génétique Médicale [CHU Toulouse]
26 ToNIC - Toulouse NeuroImaging Center
Laura J Grange
- Fonction : Auteur
- PersonId : 1418494
- ORCID : 0000-0003-0909-4341
John J Reynolds
- Fonction : Auteur
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- ORCID : 0000-0001-8690-5828
Robert F Shearer
- Fonction : Auteur
- PersonId : 1418496
- ORCID : 0000-0003-3012-8788
Ryan M Baxley
- Fonction : Auteur
- PersonId : 1418497
- ORCID : 0000-0002-3286-7990
Antony W Oliver
- Fonction : Auteur
- PersonId : 1418498
- ORCID : 0000-0002-2912-8273
Sophie L Cooke
- Fonction : Auteur
- PersonId : 1418499
- ORCID : 0000-0001-8169-8735
Satpal S Jhujh
- Fonction : Auteur
- PersonId : 1418500
- ORCID : 0000-0001-5766-659X
Martin R Higgs
- Fonction : Auteur
- PersonId : 1418501
- ORCID : 0000-0002-8218-0089
Tahir Khan
- Fonction : Auteur
- PersonId : 1418502
- ORCID : 0000-0003-3096-8795
Gabriel Á Martos-Moreno
- Fonction : Auteur
Sharon Chupp
- Fonction : Auteur
Christopher G Mathew
- Fonction : Auteur
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- ORCID : 0000-0003-4178-1838
David Parry
- Fonction : Auteur
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- ORCID : 0000-0003-0376-7736
Michael A Simpson
- Fonction : Auteur
- PersonId : 1418505
- ORCID : 0000-0002-8539-8753
Saad Ahmed Seth
- Fonction : Auteur
- PersonId : 1418507
- ORCID : 0000-0002-0570-2031
Karlla W Brigatti
- Fonction : Auteur
Alexander P A Stegmann
- Fonction : Auteur
- PersonId : 1212289
- ORCID : 0000-0002-9736-7137
Masato Kanemaki
- Fonction : Auteur
- PersonId : 1182559
- ORCID : 0000-0002-7657-1649
Dragana Josifova
- Fonction : Auteur
- PersonId : 1418508
- ORCID : 0000-0001-7634-9207
Yuri Uchiyama
- Fonction : Auteur
- PersonId : 1418509
- ORCID : 0000-0002-4540-5277
Hitoshi Osaka
- Fonction : Auteur
- PersonId : 1418510
- ORCID : 0000-0002-1320-1165
Zineb Ammous
- Fonction : Auteur
Jesús Argente
- Fonction : Auteur
- PersonId : 1418511
- ORCID : 0000-0001-5826-0276
Naomichi Matsumoto
- Fonction : Auteur
- PersonId : 1252291
- ORCID : 0000-0001-9846-6500
Alexander M R Taylor
- Fonction : Auteur
- PersonId : 1418512
- ORCID : 0000-0002-7818-7595
Anja-Katrin Bielinsky
- Fonction : Auteur
- PersonId : 1418513
- ORCID : 0000-0003-1783-619X
Niels Mailand
- Fonction : Auteur
- PersonId : 1418514
- ORCID : 0000-0002-6623-709X
Cedric Le Caignec
- Fonction : Auteur
- PersonId : 1333299
- ORCID : 0000-0002-0598-653X
Erica E Davis
- Fonction : Auteur
- PersonId : 1384737
- ORCID : 0000-0002-2412-8397
Grant S Stewart
- Fonction : Auteur
- PersonId : 1418515
- ORCID : 0000-0002-0960-3241
Résumé
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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