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

den Hoed, Joery; de Boer, Elke; Voisin, Norine; Dingemans, Alexander J M; Guex, Nicolas; Wiel, Laurens; Nellaker, Christoffer; Amudhavalli, Shivarajan M; Banka, Siddharth; Bena, Frederique S; Ben-Zeev, Bruria; Bonagura, Vincent R; Bruel, Ange-Line; Brunet, Theresa; Brunner, Han G; Chew, Hui B; Chrast, Jacqueline; Cimbalistienė, Loreta; Coon, Hilary; Délot, Emmanuèlle C; Démurger, Florence; Denommé-Pichon, Anne-Sophie; Depienne, Christel; Donnai, Dian; Dyment, David A; Elpeleg, Orly; Faivre, Laur...     »

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.      «

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 path...     »