Am J Hum Genet. 2021 Jan 26;S0002-9297(21)00007-0. doi: 10.1016/j.ajhg.2021.01.007. Online ahead of print.
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
Joery den Hoed 1, Elke de Boer 2, Norine Voisin 3, Alexander J M Dingemans 2, Nicolas Guex 4, Laurens Wiel 5, Christoffer Nellaker 6, Shivarajan M Amudhavalli 7, Siddharth Banka 8, Frederique S Bena 9, Bruria Ben-Zeev 10, Vincent R Bonagura 11, Ange-Line Bruel 12, Theresa Brunet 13, Han G Brunner 14, Hui B Chew 15, Jacqueline Chrast 3, Loreta Cimbalistienė 16, Hilary Coon 17, DDD Study; Emmanuèlle C Délot 18, Florence Démurger 19, Anne-Sophie Denommé-Pichon 12, Christel Depienne 20, Dian Donnai 8, David A Dyment 21, Orly Elpeleg 22, Laurence Faivre 23, Christian Gilissen 24, Leslie Granger 25, Benjamin Haber 26, Yasuo Hachiya 27, Yasmin Hamzavi Abedi 28, Jennifer Hanebeck 26, Jayne Y Hehir-Kwa 29, Brooke Horist 30, Toshiyuki Itai 31, Adam Jackson 32, Rosalyn Jewell 33, Kelly L Jones 34, Shelagh Joss 35, Hirofumi Kashii 27, Mitsuhiro Kato 36, Anja A Kattentidt-Mouravieva 37, Fernando Kok 38, Urania Kotzaeridou 26, Vidya Krishnamurthy 30, Vaidutis Kučinskas 16, Alma Kuechler 20, Alinoë Lavillaureix 39, Pengfei Liu 40, Linda Manwaring 41, Naomichi Matsumoto 31, Benoît Mazel 42, Kirsty McWalter 43, Vardiella Meiner 22, Mohamad A Mikati 44, Satoko Miyatake 31, Takeshi Mizuguchi 31, Lip H Moey 45, Shehla Mohammed 46, Hagar Mor-Shaked 22, Hayley Mountford 47, Ruth Newbury-Ecob 48, Sylvie Odent 39, Laura Orec 26, Matthew Osmond 21, Timothy B Palculict 43, Michael Parker 49, Andrea K Petersen 25, Rolph Pfundt 50, Eglė Preikšaitienė 16, Kelly Radtke 51, Emmanuelle Ranza 52, Jill A Rosenfeld 53, Teresa Santiago-Sim 43, Caitlin Schwager 7, Margje Sinnema 54, Lot Snijders Blok 55, Rebecca C Spillmann 56, Alexander P A Stegmann 57, Isabelle Thiffault 58, Linh Tran 44, Adi Vaknin-Dembinsky 59, Juliana H Vedovato-Dos-Santos 60, Samantha A Schrier Vergano 61, Eric Vilain 18, Antonio Vitobello 12, Matias Wagner 62, Androu Waheeb 63, Marcia Willing 41, Britton Zuccarelli 64, Usha Kini 65, Dianne F Newbury 47, Tjitske Kleefstra 2, Alexandre Reymond 3, Simon E Fisher 66, Lisenka E L M Vissers 2Affiliations expand
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.
Keywords: HPO-based analysis; SATB1; cell-based functional assays; de novo variants; intellectual disability; neurodevelopmental disorders; seizures; teeth abnormalities.
- PMID: 33513338
- DOI: 10.1016/j.ajhg.2021.01.007