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

• Published in: Nature communications Vol. 13; no. 1; pp. 6664 - 22
• Main Authors: 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 Á., 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.11.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/44; 13/89; 14/32; 14/63; 631/208/211; 631/208/366; 631/80/103; 631/80/641/151; 82/29; 96/106; 96/31; 96/35; Abnormalities; Anemia; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell differentiation; Cell division; Chromosomal Proteins, Non-Histone - metabolism; Chromosomes; Chromosomes - metabolism; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA repair; DNA Repair - genetics; DNA-Binding Proteins - metabolism; Embryogenesis; Embryonic growth stage; Genomes; Genomic Instability; Humanities and Social Sciences; Humans; Life Sciences; Microcephaly; Microcephaly - genetics; Microencephaly; Mosaics; multidisciplinary; Mutation; Neurodevelopmental disorders; Phenotypes; Replication; Science; Science (multidisciplinary); Stability; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-34349-8

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. The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy.