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

Journal: American Journal Of Human Genetics
Published:
Abstract

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. In contrast, 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, 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.

Authors
Joery Den Hoed, Elke De Boer, Norine Voisin, Alexander J Dingemans, Nicolas Guex, Laurens Wiel, Christoffer Nellaker, Shivarajan Amudhavalli, Siddharth Banka, Frederique Bena, Bruria Ben Zeev, Vincent Bonagura, Ange-line Bruel, Theresa Brunet, Han Brunner, Hui Chew, Jacqueline Chrast, Loreta Cimbalistienė, Hilary Coon, Florence Démurger, Anne-sophie Denommé Pichon, Christel Depienne, Dian Donnai, David Dyment, Orly Elpeleg, Laurence Faivre, Christian Gilissen, Leslie Granger, Benjamin Haber, Yasuo Hachiya, Yasmin Abedi, Jennifer Hanebeck, Jayne Hehir Kwa, Brooke Horist, Toshiyuki Itai, Adam Jackson, Rosalyn Jewell, Kelly Jones, Shelagh Joss, Hirofumi Kashii, Mitsuhiro Kato, Anja 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 Mikati, Satoko Miyatake, Takeshi Mizuguchi, Lip Moey, Shehla Mohammed, Hagar Mor Shaked, Hayley Mountford, Ruth Newbury Ecob, Sylvie Odent, Laura Orec, Matthew Osmond, Timothy Palculict, Michael Parker, Andrea Petersen, Rolph Pfundt, Eglė Preikšaitienė, Kelly Radtke, Emmanuelle Ranza, Jill Rosenfeld, Teresa Santiago Sim, Caitlin Schwager, Margje Sinnema, Lot Snijders Blok, Rebecca Spillmann, Alexander P Stegmann, Isabelle Thiffault, Linh Tran, Adi Vaknin Dembinsky, Juliana Vedovato Dos Santos, Samantha Schrier Vergano, Eric Vilain, Antonio Vitobello, Matias Wagner, Androu Waheeb, Marcia Willing, Britton Zuccarelli, Usha Kini, Dianne Newbury, Tjitske Kleefstra, Alexandre Reymond, Simon Fisher, Lisenka E L Vissers
Relevant Conditions

Seizures