Title

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

Creator(s)

Joery den Hoed
Elke de Boer
Norine Voisin
Alexander J M Dingemans
Nicolas Guex
Laurens Wiel
Christoffer Nellaker
Shivarajan Manickavasagam Amudhavalli, Children's Mercy HospitalFollow
Siddharth Banka
Frederique S. Bena
Bruria Ben-Zeev
Vincent R. Bonagura
Ange-Line Bruel
Theresa Brunet
Han G. Brunner
Hui B. Chew
Jacqueline Chrast
Loreta Cimbalistienė
Hilary Coon
DDD Study
Emmanuèlle C. Délot
Florence Démurger
Anne-Sophie Denommé-Pichon
Christel Depienne
Dian Donnai
David A. Dyment
Orly Elpeleg
Laurence Faivre
Christian Gilissen
Leslie Granger
Benjamin Haber
Yasuo Hachiya
Yasmin Hamzavi Abedi
Jennifer Hanebeck
Jayne Y. Hehir-Kwa
Brooke Horist
Toshiyuki Itai
Adam Jackson
Rosalyn Jewell
Kelly L. Jones
Shelagh Joss
Hirofumi Kashii
Mitsuhiro Kato
Anja A. Kattentidt-Mouravieva
Fernando Kok
Urania Kotzaeridou
Vidya Krishnamurthy
Vaidutis Kučinskas
Alma Kuechler
Alinoë Lavillaureix
Pengfei Liu
Linda Manwaring
Naomichi Matsumoto
Benoît Mazel
Kirsty McWalter
Vardiella Meiner
Mohamad A. Mikati
Satoko Miyatake
Takeshi Mizuguchi
Lip H. Moey
Shehla Mohammed
Hagar Mor-Shaked
Hayley Mountford
Ruth Newbury-Ecob
Sylvie Odent
Laura Orec
Matthew Osmond
Timothy B. Palculict
Michael Parker
Andrea K. Petersen
Rolph Pfundt
Eglė Preikšaitienė
Kelly Radtke
Emmanuelle Ranza
Jill A. Rosenfeld
Teresa Santiago-Sim
Caitlin Schwager
Margje Sinnema
Lot Snijders Blok
Rebecca C. Spillmann
Alexander P A Stegmann
Isabelle Thiffault, Children's Mercy HospitalFollow
Linh Tran
Adi Vaknin-Dembinsky
Juliana H. Vedovato-Dos-Santos
Samantha A. Schrier Vergano
Eric Vilain
Antonio Vitobello
Matias Wagner
Androu Waheeb
Marcia Willing
Britton Zuccarelli
Usha Kini
Dianne F. Newbury
Tjitske Kleefstra
Alexandre Reymond
Simon E. Fisher
Lisenka E L M Vissers

Document Type

Article

Publication Date

2-4-2021

Identifier

DOI: 10.1016/j.ajhg.2021.01.007; PMCID: PMC7895900

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.

Journal Title

American journal of human genetics

Volume

108

Issue

2

First Page

346

Last Page

356

MeSH Keywords

Chromatin; Female; Genetic Association Studies; Haploinsufficiency; Humans; Male; Matrix Attachment Region Binding Proteins; Models, Molecular; Mutation; Mutation, Missense; Neurodevelopmental Disorders; Protein Binding; Protein Domains; Transcription, Genetic

Keywords

HPO-based analysis; SATB1; cell-based functional assays; de novo variants; intellectual disability; neurodevelopmental disorders; seizures; teeth abnormalities

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