Phenotypic Spectrum in Individuals With Pathogenic GABRG2 Loss- and Gain-of-Function Variants.

IF 7.7 1区 医学 Q1 CLINICAL NEUROLOGY
Neurology Pub Date : 2025-07-22 Epub Date: 2025-06-26 DOI:10.1212/WNL.0000000000213644
Alessandra Rossi, Susan X N Lin, Nathan L Absalom, Sebastian Ortiz-De la Rosa, Vivian W Y Liao, Nazanin A Mohammadi, Sindhu Viswanathan, Tommy Stödberg, Alberto Danieli, Paolo Bonanni, Alec Aeby, Alessandro Orsini, Alice Bonuccelli, Andrea Rüegger, Beatriz G Giraldez, Bertrand Isidor, Burkhard Stüve, Carla Marini, Elisabetta Cesaroni, Christina D Fenger, Christophe Philippe, Colombine Meunier, Damien Lederer, Stéphanie Moortgat, Egidio Spinelli, Elisa Fallica, Fiona Zeiner, Matthias Bauman, Laura Licchetta, Francesca Bisulli, Francesca F Operto, Ira Benkel-Herrenbrueck, Kathleen M Gorman, Katrine M Johannesen, Konrad Platzer, Franziska Schnabel, Lieven Lagae, Mirjam Laufs, Riina Zordania, Stephen Malone, Tullio Messana, Wendy Werckx, Charlotta Jonsson, Zaid Afawi, Thomas Foiadelli, Yosra Halleb, Radka Stoeva, Mélanie Jennesson-Lyver, Gaetan Lesca, Renzo Guerrini, Samuel F Berkovic, Ingrid E Scheffer, Mary Chebib, Elena Gardella, Rikke S Møller, Guido Rubboli, Philip K Ahring
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引用次数: 0

Abstract

Background and objectives: Variants in the GABRG2 gene encoding the γ2 subunit of the γ-aminobutyric acid type A (GABAA) receptor are associated with a spectrum of epilepsy phenotypes. These range from simple febrile seizures to more severe conditions, including developmental and epileptic encephalopathies (DEEs). Despite previous analyses suggesting that pathogenic variants may lead to loss-of-function (LoF) receptors, a correlation between functional analysis and clinical phenotypic diversity remains elusive. We, therefore, aimed to determine why variants in the GABRG2 gene can lead to highly diverse phenotypes.

Methods: We assembled a cohort of unreported probands carrying presumed pathogenic GABRG2 variants. Electroclinical information was systematically collected, and electrophysiologic measurements were conducted for missense variants to explore potential alterations in receptor function.

Results: We examined 44 individuals with 35 GABRG2 variants (18 null and 17 missense). Functional assessments of the missense variants revealed that 9 caused LoF and 3 caused gain-of-function (GoF). The remaining 5 did not alter receptor function and are likely not pathogenic. Based on functional analysis and electroclinical data, 37 affected individuals were categorized into 3 groups: null LoF, missense LoF, and GoF variants. Among 19 individuals with null variants, epilepsy was diagnosed in 13, with a median onset of 14 months. The remaining 6 of 19 only had febrile seizures. Developmental delay/intellectual disability (DD/ID) was observed in 1 of 19 and psychiatric features in 4 of 18. By contrast, all 12 individuals with missense LoF variants suffered from epilepsy with a median onset of 15 months. Most common epilepsy diagnoses were febrile seizures plus in 4 of 12 and DEE in 4 of 12. DD/ID affected 9 of 12, and psychiatric features were diagnosed in 8 of 12. Statistical comparisons revealed that null variants were associated with a milder phenotype than missense LoF variants. Finally, 5 of 6 individuals with GoF variants had DEE characterized by early infancy onset at 2 months and severe/profound DD/ID. The sixth individual exhibited mild DD/ID and hypotonia without seizures.

Discussion: Our findings indicate that the severity of disease associated with pathogenic GABRG2 variants depends on the functional consequences of the variants. Null variants are associated with a mild phenotype and missense LoF variants with an intermediate phenotype while GoF variants can lead to severe phenotypes.

致病性GABRG2丧失和功能获得变异个体的表型谱。
背景和目的:编码γ-氨基丁酸A型(GABAA)受体γ- 2亚基的GABRG2基因变异与癫痫表型谱有关。其范围从简单的发热性癫痫发作到更严重的情况,包括发育性和癫痫性脑病(dee)。尽管先前的分析表明致病变异可能导致LoF受体的功能丧失,但功能分析与临床表型多样性之间的相关性仍然难以捉摸。因此,我们的目的是确定为什么GABRG2基因的变异会导致高度多样化的表型。方法:我们收集了一组未报道的先证者,他们携带假定的致病GABRG2变异。系统地收集电临床信息,并对错义变异进行电生理测量,以探索受体功能的潜在改变。结果:我们检测了44个人35个GABRG2变异(18个无效,17个错义)。对错义变异的功能评估显示,9个导致LoF, 3个导致功能获得(GoF)。剩下的5个没有改变受体功能,可能没有致病性。根据功能分析和电临床数据,将37例患者分为3组:无LoF、错义LoF和GoF变异。在19名无变异个体中,13人被诊断为癫痫,中位发病时间为14个月。其余6例只有发热性惊厥。19人中有1人有发育迟缓/智力障碍(DD/ID), 18人中有4人有精神特征。相比之下,所有12名LoF错义变异患者都患有癫痫,中位发病时间为15个月。最常见的癫痫诊断是12例中有4例为发热性癫痫发作,12例中有4例为DEE。12人中有9人患有DD/ID,其中8人被诊断为精神特征。统计比较显示,与错义LoF变异相比,null变异与更温和的表型相关。最后,6例GoF变异个体中有5例DEE的特征是2个月时婴儿期早期发病和严重/深度DD/ID。第六例患者表现为轻度DD/ID和张力低下,无癫痫发作。讨论:我们的研究结果表明,与致病性GABRG2变异相关的疾病严重程度取决于变异的功能后果。Null变异与轻度表型相关,错义LoF变异与中等表型相关,而GoF变异可能导致严重表型。
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来源期刊
Neurology
Neurology 医学-临床神经学
CiteScore
12.20
自引率
4.00%
发文量
1973
审稿时长
2-3 weeks
期刊介绍: Neurology, the official journal of the American Academy of Neurology, aspires to be the premier peer-reviewed journal for clinical neurology research. Its mission is to publish exceptional peer-reviewed original research articles, editorials, and reviews to improve patient care, education, clinical research, and professionalism in neurology. As the leading clinical neurology journal worldwide, Neurology targets physicians specializing in nervous system diseases and conditions. It aims to advance the field by presenting new basic and clinical research that influences neurological practice. The journal is a leading source of cutting-edge, peer-reviewed information for the neurology community worldwide. Editorial content includes Research, Clinical/Scientific Notes, Views, Historical Neurology, NeuroImages, Humanities, Letters, and position papers from the American Academy of Neurology. The online version is considered the definitive version, encompassing all available content. Neurology is indexed in prestigious databases such as MEDLINE/PubMed, Embase, Scopus, Biological Abstracts®, PsycINFO®, Current Contents®, Web of Science®, CrossRef, and Google Scholar.
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