Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.
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.
den Hoed, J; de Boer, E; Voisin, N; Dingemans, AJM; Guex, N; Wiel, L; Nellaker, C; Amudhavalli, SM; Banka, S; Bena, FS; Ben-Zeev, B; Bonagura, VR; Bruel, A-L; Brunet, T; Brunner, HG; Chew, HB; Chrast, J; Cimbalistienė, L; Coon, H; DDD Study, ; Délot, EC; Démurger, F; Denommé-Pichon, A-S; Depienne, C; Donnai, D; Dyment, DA; Elpeleg, O; Faivre, L; Gilissen, C; Granger, L; Haber, B; Hachiya, Y; Abedi, YH; Hanebeck, J; Hehir-Kwa, JY; Horist, B; Itai, T; Jackson, A; Jewell, R; Jones, KL; Joss, S; Kashii, H; Kato, M; Kattentidt-Mouravieva, AA; Kok, F; Kotzaeridou, U; Krishnamurthy, V; Kučinskas, V; Kuechler, A; Lavillaureix, A; Liu, P; Manwaring, L; Matsumoto, N; Mazel, B; McWalter, K; Meiner, V; Mikati, MA; Miyatake, S; Mizuguchi, T; Moey, LH; Mohammed, S; Mor-Shaked, H; Mountford, H; Newbury-Ecob, R; Odent, S; Orec, L; Osmond, M; Palculict, TB; Parker, M; Petersen, AK; Pfundt, R; Preikšaitienė, E; Radtke, K; Ranza, E; Rosenfeld, JA; Santiago-Sim, T; Schwager, C; Sinnema, M; Snijders Blok, L; Spillmann, RC; Stegmann, APA; Thiffault, I; Tran, L; Vaknin-Dembinsky, A; Vedovato-Dos-Santos, JH; Schrier Vergano, SA; Vilain, E; Vitobello, A; Wagner, M; Waheeb, A; Willing, M; Zuccarelli, B; Kini, U; Newbury, DF; Kleefstra, T; Reymond, A; Fisher, SE; Vissers, LELM
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