PDF(Pubmed)
Abstract：
BACKGROUND: Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants.
METHODS: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function.
RESULTS: Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants.
CONCLUSIONS: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes.
BACKGROUND: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.
METHODS: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function.
RESULTS: Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants.
CONCLUSIONS: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes.
BACKGROUND: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.
摘要：
背景：GABRB2中的变体，编码γ-氨基丁酸A型（GABAA）受体的β2亚基，会导致各种各样的条件，从高热惊厥到严重的发育性和癫痫性脑病。然而,发展为轻度和更严重疾病的潜在风险机制尚不清楚.在这项研究中,我们在一组GABRB2变异个体中进行了全面的基因型-表型相关性分析.
方法：收集了42名携带26种不同GABRB2变体的个体的遗传和电临床数据，并伴随着这些变体对受体功能影响的电生理学分析。
结果：对α1β2γ2受体的电生理学评估显示，25/26变体导致核心受体特性如GABA敏感性的功能障碍。其中,17产生功能获得(GOF),而8产生功能丧失性状(LOF)。基因型-表型相关分析显示，携带GOF变异的个体患有严重的发育迟缓/智力障碍（DD/ID，74%），运动障碍，如肌张力障碍或运动障碍（59％），小头畸形（50％）和早期死亡的高风险（26％）。相反，LOF变异与轻度疾病表现相关。具有这些变异的个体通常表现出发烧引发的癫痫发作（92％），较温和的DD/ID度(85%)，并保持步行功能(85%)。值得注意的是,在有功能丧失变异的个体中未报告严重运动障碍或小头畸形.
结论：数据显示，GABRB2中的遗传变异可导致功能的获得和丧失，这种差异与不同的疾病表现有关。利用这些信息，我们构建了一个诊断流程图,通过考虑临床表型,帮助预测最近鉴定的变异的致病性.
背景：这项工作由澳大利亚国家卫生与医学研究委员会资助，诺和诺德基金会和伦德贝克基金会.
方法：收集了42名携带26种不同GABRB2变体的个体的遗传和电临床数据，并伴随着这些变体对受体功能影响的电生理学分析。
结果：对α1β2γ2受体的电生理学评估显示，25/26变体导致核心受体特性如GABA敏感性的功能障碍。其中,17产生功能获得(GOF),而8产生功能丧失性状(LOF)。基因型-表型相关分析显示，携带GOF变异的个体患有严重的发育迟缓/智力障碍（DD/ID，74%），运动障碍，如肌张力障碍或运动障碍（59％），小头畸形（50％）和早期死亡的高风险（26％）。相反，LOF变异与轻度疾病表现相关。具有这些变异的个体通常表现出发烧引发的癫痫发作（92％），较温和的DD/ID度(85%)，并保持步行功能(85%)。值得注意的是,在有功能丧失变异的个体中未报告严重运动障碍或小头畸形.
结论：数据显示，GABRB2中的遗传变异可导致功能的获得和丧失，这种差异与不同的疾病表现有关。利用这些信息，我们构建了一个诊断流程图,通过考虑临床表型,帮助预测最近鉴定的变异的致病性.
背景：这项工作由澳大利亚国家卫生与医学研究委员会资助，诺和诺德基金会和伦德贝克基金会.
