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

J. den Hoed, E. de Boer, N. Voisin, A.J.M. Dingemans, N. Guex, L. Wiel, C. Nellaker, S.M. Amudhavalli, S. Banka, F.S. Bena, B. Ben-Zeev, V.R. Bonagura, A.L. Bruel, T. Brunet, H.G. Brunner, H.B. Chew, J. Chrast, L. Cimbalistiene, H. Coon, E.C. DelotF. Demurger, A.S. Denomme-Pichon, C. Depienne, D. Donnai, D.A. Dyment, O. Elpeleg, L. Faivre, C. Gilissen, L. Granger, B. Haber, Y. Hachiya, Y.H. Abedi, J. Hanebeck, J.Y. Hehir-Kwa, B. Horist, T. Itai, A. Jackson, R. Jewell, K.L. Jones, S. Joss, H. Kashii, M. Kato, A.A. Kattentidt-Mouravieva, F. Kok, U. Kotzaeridou, V. Krishnamurthy, V. Kucinskas, A. Kuechler, A. Lavillaureix, P.F. Liu, DDD Study, Simon E. Fisher*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Web of Science)


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.
Original languageEnglish
Pages (from-to)346-356
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number2
Publication statusPublished - 4 Feb 2021



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