当前位置: X-MOL 学术Genet. Med. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome
Genetics in Medicine ( IF 6.6 ) Pub Date : 2021-08-03 , DOI: 10.1038/s41436-021-01246-2
Marjolein J A Weerts 1 , Kristina Lanko 1 , Francisco J Guzmán-Vega 2 , Adam Jackson 3, 4 , Reshmi Ramakrishnan 2 , Kelly J Cardona-Londoño 2 , Karla A Peña-Guerra 2 , Yolande van Bever 1 , Barbara W van Paassen 1 , Anneke Kievit 1 , Marjon van Slegtenhorst 1 , Nicholas M Allen 5 , Caroline M Kehoe 5 , Hannah K Robinson 6 , Lewis Pang 6 , Selina H Banu 7 , Mashaya Zaman 7 , Stephanie Efthymiou 8 , Henry Houlden 8 , Irma Järvelä 9 , Leena Lauronen 10 , Tuomo Määttä 11 , Isabelle Schrauwen 12 , Suzanne M Leal 12 , Claudia A L Ruivenkamp 13 , Daniela Q C M Barge-Schaapveld 13 , Cacha M P C D Peeters-Scholte 14 , Hamid Galehdari 15 , Neda Mazaheri 15 , Sanjay M Sisodiya 16, 17 , Victoria Harrison 18 , Angela Sun 19 , Jenny Thies 20 , Luis Alberto Pedroza 21 , Yana Lara-Taranchenko 22 , Ivan K Chinn 23, 24 , James R Lupski 25, 26, 27 , Alexandra Garza-Flores 28 , Jeffery McGlothlin 29 , Lin Yang 30 , Shaoping Huang 30 , Xiaodong Wang 31 , Tamison Jewett 32 , Gretchen Rosso 32 , Xi Lin 33 , Shehla Mohammed 34 , J Lawrence Merritt 19 , Ghayda M Mirzaa 19, 35, 36 , Andrew E Timms 37 , Joshua Scheck 35 , Mariet W Elting 38 , Abeltje M Polstra 38 , Lauren Schenck 39 , Maura R Z Ruzhnikov 39, 40 , Annalisa Vetro 41 , Martino Montomoli 41 , Renzo Guerrini 41 , Daniel C Koboldt 42 , Theresa Mihalic Mosher 42 , Matthew T Pastore 42 , Kim L McBride 42 , Jing Peng 43 , Zou Pan 43 , Marjolein Willemsen 44 , Susanne Koning 45 , Peter D Turnpenny 46 , Bert B A de Vries 44 , Christian Gilissen 44 , Rolph Pfundt 44 , Melissa Lees 47 , Stephen R Braddock 48 , Kara C Klemp 48 , Fleur Vansenne 49 , Marielle E van Gijn 49 , Catherine Quindipan 50 , Matthew A Deardorff 50, 51 , J Austin Hamm 52 , Abbey M Putnam 52 , Rebecca Baud 53 , Laurence Walsh 53, 54 , Sally A Lynch 55 , Julia Baptista 6, 56 , Richard E Person 57 , Kristin G Monaghan 57 , Amy Crunk 57 , Jennifer Keller-Ramey 57 , Adi Reich 57 , Houda Zghal Elloumi 57 , Marielle Alders 58 , Jennifer Kerkhof 59 , Haley McConkey 59 , Sadegheh Haghshenas 60 , , Reza Maroofian 8 , Bekim Sadikovic 59, 60 , Siddharth Banka 3, 4 , Stefan T Arold 2, 61 , Tahsin Stefan Barakat 1
Affiliation  

Purpose

Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort.

Methods

We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays.

Results

Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants.

Conclusion

Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.



中文翻译:

描绘 SETD1B 相关综合征的分子和表型谱

目的

SETD1B的致病性变异与包括智力障碍、语言延迟和癫痫发作在内的综合性神经发育障碍有关。迄今为止,已经描述了 11 名具有(可能)致病性SETD1B序列变异的患者的临床特征。本研究旨在基于扩展患者队列的特征,进一步描述SETD1B相关综合征的谱系。

方法

我们对一组 36 名未发表的具有SETD1B序列变异的个体进行了深入的临床表征,描述了他们的分子和表型谱。使用体外和全基因组甲基化测定对选定的变体进行功能测试。

结果

我们的数据提供了SETD1B变体功能丧失机制的证据,导致全球发育迟缓、语言迟缓(包括退化、智力残疾、自闭症和其他行为问题)以及可变癫痫表型的核心临床表型。发育迟缓似乎先于癫痫发作,这表明即使在没有癫痫活动的情况下,SETD1B 功能障碍也会影响生理神经发育。男性显着过多且受影响更严重,我们推测性相关性状可能会影响外显率的易感性和SETD1B变体的临床谱。

结论

从这个广泛的队列中获得的见解将有助于对新诊断的患有SETD1B相关综合征的患者的分子和表型景观进行咨询。

更新日期:2021-08-03
down
wechat
bug