Centre for Clinical Genetics, Sydney Children's Hospital Network, Randwick, NSW, Australia.
Discipline of Paediatrics and Child Health, Faculty of Medicine and Health, University of New South Wales, Randwick, NSW, Australia.
Mol Psychiatry. 2023 Feb;28(2):668-697. doi: 10.1038/s41380-022-01852-9. Epub 2022 Nov 16.
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
X 染色体连锁的 CLCN4 基因中的错义突变和截断突变,导致编码氯离子/质子转运体 ClC-4 的功能降低或完全丧失(LOF),最近被证明会导致男性和女性出现神经认知表型。通过国际临床匹配和公共变异数据库的查询,我们在 90 个家庭中收集了 90 个罕见的 CLCN4 错义变异体的数据库:49 个家庭中有 41 个独特的变异体和 18 个重复的变异体。对于包括 22 名男性和 33 名女性在内的 43 个家庭,我们整理了详细的临床和分离数据。为了确认变异体的因果关系并深入了解疾病机制,我们在 Xenopus oocytes 中使用扩展的电压和 pH 范围,对 59 个变体的电生理特性进行了研究。详细分析揭示了新的病理生理学机制:25%(15/59)的变体表现出 LOF,其特征是电压依赖性激活向更正的电压“转移”,并且有九个变体导致毒性获得功能,与破坏的门相关联,允许在负电压下进行内向转运。功能结果并不总是与计算机预测的致病性评分一致,这突出了准确遗传咨询中对致病性评估的复杂性。讨论了这种情况的复杂神经认知和精神表现,以及迄今为止对生长、胃肠道功能和运动控制的认识不足的影响。包括已发表的病例,我们总结了 67 个家庭中 122 名与 CLCN4 相关的神经发育障碍个体的特征,并提出了未来的研究方向,旨在改善对该诊断个体的综合护理。