Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction

Joery den Hoed, Elke de Boer, N Voisin, A Dingemans, N Guex, L Wiel, C Nellaker, S Amudhavalli, S Banka, F Bena, B Ben-Zeev, V Bonagura, A Bruel, T Brunet, H. G. Brunner, H. B. Chew, J. Chrast, Loreta Cimbalistienė, Hilary Coon, The DDD studyEmmanuèlle C Délot, Florence Démurger, Anne-Sophie Denommé-Pichon, C. Depienne, Dian Donnai, David A Dyment, Orly Elpeleg, L Faivre, Christian Gilissen, L. Granger, Benjamin Haber, Yasuo Hachiya, Yasmin Hamzavi Abedi, Jennifer Hanebeck, Jayne Y Hehir-Kwa, Brooke Horist, Toshiyuki Itai, Adam Jackson, Rosalyn Jewell, Kelly L. Jones, Shelagh Joss, Hirofumi Kashii, Mitsuhiro Kato, Anja A Kattentidt-Mouravieva, Fernando Kok, Urania Kotzaeridou, Vidya Krishnamurthy, Vaidutis Kučinskas, Alma Kuechler, Alinoë Lavillaureix, Pengfei Liu, Linda Manwaring, Naomichi Matsumoto, Benoît Mazel, Kirsty McWalter, Vardiella Meiner, Mohamad A. Mikati, Satoko Miyatake, Takeshi Mizuguchi, Lip H. Moey, Shehla Mohammed, Hagar Mor-Shaked, Hayley Mountford, Ruth Newbury-Ecob, Sylvie Odent, Laura Orec, Matthew Osmond, Timothy Blake Palculict, Michael Parker, Andrea K. Petersen, Rolph Pfundt, Eglė Preikšaitienė, Kelly Radtke, Emmanuelle Ranza, Jill A. Rosenfeld, Teresa Santiago-Sim, Caitlin Schwager, Margje Sinnema, Lot Snijders Blok, Rebecca C. Spillmann, Alexander P A Stegmann, Isabelle Thiffault, Linh Tran, Adi Vaknin-Dembinsky, Juliana H. Vedovato-dos-Santos, Samantha A. Schrier Vergano, Eric Vilain, Antonio Vitobello, Matias Wagner, Androu Waheeb, Marcia C. Willing, Britton D Zuccarelli, Usha Kini, Dianne F. Newbury, Tjitske Kleefstra, Alexandre Reymond, Simon E. Fisher, Lisenka E L M Vissers

Research output: Working paperPreprint


Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. Contrastingly, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay and encode truncated proteins, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
Original languageEnglish
Number of pages24
Publication statusPublished - 24 Oct 2020


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