SMARCA1基因的致病性变异会导致一种受NURF复合物组成调节的X连锁神经发育障碍。
Pathogenic variants in SMARCA1 cause an X-linked neurodevelopmental disorder modulated by NURF complex composition.
作者信息
Picketts David, Mirzaa Ghayda, Yan Keqin, Relator Raissa, Timpano Sara, Yalcin Binnaz, Collins Stephan, Ziegler Alban, Pao Emily, Oyama Nora, Brischoux-Boucher Elise, Piard Juliette, Monaghan Kristin, Sacoto Maria Guillen, Dobyns William, Park Kristen, Fernández-Mayoralas Daniel, Fernández-Jaén Alberto, Jayakar Parul, Brusco Alfredo, Antona Vincenzo, Giorgio Elisa, Kvarnung Malin, Isidor Bertrand, Conrad Solène, Cogné Benjamin, Deb Wallid, Stuurman K E, Sterbova Katalin, Smal Noor, Weckhuysen Sarah, Oegema Renske, Innes Micheil, Latsko Maeson, Ben-Omran Tawfeg, Yeh Rebecca, Kruer Michael, Bakhtiari Somayeh, Papavasiliou Antigone, Moutton Sébastien, Nambot Sophie, Chanprasert Sirisak, Paolucci Sarah, Miller Kait, Burton Barbara, Kim Katherine, O'Heir Emily, Bruwer Zandre, Donald Kirsten, Kleefstra Tjitske, Goldstein Amy, Angle Brad, Bontempo Kelly, Miny Peter, Joset Pascal, Demurger Florence, Hobson Emma, Pang Lewis, Carpenter Lori, Li Dong, Bonneau Dominique, Sadikovic Bekim
机构信息
Ottawa Hospital Research Institute.
Seattle Children's Hospital.
出版信息
Res Sq. 2023 Sep 29:rs.3.rs-3317938. doi: 10.21203/rs.3.rs-3317938/v1.
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 SNF2H () or SNF2L () ISWI-chromatin remodeling enzyme. Pathogenic variants in and were previously implicated in NDDs. Here, we describe 40 individuals from 30 families with or maternally inherited pathogenic variants in . This novel NDD was associated with mild to severe ID/DD, delayed or regressive speech development, and some recurrent facial dysmorphisms. Individuals carrying loss-of-function variants exhibited a mild genome-wide DNA methylation profile and a high penetrance of macrocephaly. Genetic dissection of the NURF complex using , and and double mouse knockouts revealed the importance of NURF composition and dosage for proper forebrain development. Finally, we propose that genetic alterations affecting different NURF components result in a NDD with a broad clinical spectrum.
ATP 依赖性染色质重塑蛋白中的致病变异是神经发育障碍（NDDs）的常见病因。NURF 复合物由 BPTF 和 SNF2H（）或 SNF2L（）ISWI 染色质重塑酶组成。和中的致病变异先前已被认为与 NDDs 有关。在此，我们描述了来自 30 个家庭的 40 名个体，他们携带或母系遗传的致病变异。这种新型 NDD 与轻度至重度智力障碍/发育迟缓、言语发育延迟或倒退以及一些反复出现的面部畸形有关。携带功能丧失变异的个体表现出轻度的全基因组 DNA 甲基化谱和高比例的巨头症。使用、和双基因敲除小鼠对 NURF 复合物进行基因剖析，揭示了 NURF 组成和剂量对正常前脑发育的重要性。最后，我们提出影响不同 NURF 成分的基因改变会导致具有广泛临床谱的 NDD。
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