Am J Hum Genet. 2021 Feb 4;108(2):346-356. doi: 10.1016/j.ajhg.2021.01.007. Epub 2021 Jan 28.

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

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.

• PMID: 33513338
• DOI: 10.1016/j.ajhg.2021.01.007