Am J Hum Genet.: co-auth.: group Reymond

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

Abstract

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.