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.
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.