Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition

作者：Ghayda Mirzaa, Keqin Yan, Raissa Relator, Mathieu Lévesque, P.S. Jayasinghe, Sara Timpano, Binnaz Yalcin, Stephan C. Collins, Alban Ziegler, Emily Pao, Nora Oyama, Elise Brischoux‐Boucher, Juliette Piard, Kristin G. Monaghan, María J. Guillen Sacoto, William B. Dobyns, Kristen Park, Daniel Martı́n Fernández-Mayoralas, Alberto Fernández‐Jaén, Parul Jayakar, María Palomares‐Bralo, Fernando Santos‐Simarro, Alfredo Brusco, Vincenzo Antona, Elisa Giorgio, Malin Kvarnung, Bertrand Isidor, Solène Conrad, Benjamin Cogné, Wallid Deb, Kyra E. Stuurman, Katalin Štěrbová, Noor Smal, Sarah Weckhuysen, Renske Oegema, A. Micheil Innes, Daniel C. Koboldt, Tawfeg Ben‐Omran, Rebecca C. Yeh, Michael C. Kruer, Somayeh Bakhtiari, Antigone Papavasiliou, Sébastien Moutton, Sophie Nambot, Sirisak Chanprasert, Sarah A Paolucci, K. Miller, Barbara K. Burton, Katherine Kim, Emily O’Heir, Zandrè Bruwer, Kirsten A. Donald, Tjitske Kleefstra, Amy Goldstein, Brad Angle, Kelly Bontempo, Peter Miny, Pascal Joset, Florence Démurger, Emma Hobson, Lewis Pang, Lori Carpenter, Dong Li, Dominique Bonneau, Bekim Sadiković, David J. Picketts · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64838-5 · 被引用次数：5 · 研究领域：Chromatin Remodeling and Cancer、Genomics and Rare Diseases、Genomic variations and chromosomal abnormalities

Pathogenic variants in ATP-dependent chromatin remodeling proteins are a recurrent cause of neurodevelopmental disorders (NDDs). The NURF complex consists of BPTF and either the SMARCA5 or SMARCA1 ISWI-chromatin remodeling enzyme. Pathogenic variants in BPTF and SMARCA5 have been previously implicated in NDDs. Here, we describe 35 individuals from 26 families with de novo or maternally inherited variants in the X-linked SMARCA1 gene. This SMARCA1-related NDD is associated with a spectrum of involvement, including mild to severe ID/DD, delayed or regressive speech development, ASD features, facial dysmorphisms, and other variable features. Individuals carrying SMARCA1 truncating variants exhibit a mildly unique genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using Smarca1, Smarca5, and Bptf single and double mouse knockouts reveals the importance of NURF composition and dosage for proper forebrain development. We propose that genetic alterations affecting different NURF components, including SMARCA1, result in a NDD with a broad clinical spectrum.