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, A.J.M.Guex, N.Wiel, L.Nellaker, C.Amudhavalli, S.M.Banka, S.Bena, F.S.Ben-Zeev, B.Bonagura, V.R.Bruel, A.-L.Brunet, T.Brunner, H.G.Chew, H.B.Chrast, J.Cimbalistienė, L.Coon, H.Délot, E.C.Démurger, F.Denommé-Pichon, A.-S.Depienne, C.Donnai, D.Dyment, D.A.Elpeleg, O.Faivre, L.Gilissen, C.Granger, L.Haber, B.Hachiya, Y.Abedi, Y.H.Hanebeck, J.Hehir-Kwa, J.Y.Horist, B.Itai, T.Jackson, A.Jewell, R.Jones, K.L.Joss, S.Kashii, H.Kato, M.Kattentidt-Mouravieva, A.A.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, M.A.Miyatake, S.Mizuguchi, T.Moey, L.H.Mohammed, S.Mor-Shaked, H.Mountford, H.Newbury-Ecob, R.Odent, S.Orec, L.Osmond, M.Palculict, T.B.Parker, M.Petersen, A.Pfundt, R.Preikšaitienė, E.Radtke, K.Ranza, E.Rosenfeld, J.A.Santiago-Sim, T.Schwager, C.Sinnema, M.Blok, L.S.Spillmann, R.C.Stegmann, A.P.A.Thiffault, I.Tran, L.Vaknin-Dembinsky, A.Vedovato-dos-Santos, J.H.Vergano, S.A.Vilain, E. Vitobello, A.Wagner, M.Waheeb, A.Willing, M.Zuccarelli, B.Kini, U.Newbury, D.F.Kleefstra, T.Reymond, A.Fisher, S.E.Vissers, L.E.L.M.
Department of Biological and Medical Sciences
Year of publication: Not yet published.Date of RADAR deposit: 2021-01-15