Abstract：
BACKGROUND: Raynaud-Claes syndrome is a very rare X-linked condition, characterized by intellectual disability, impaired language development, brain abnormalities, facial dysmorphisms and drug-resistant epilepsy. It is caused by loss-of-function variants in the CLCN4 gene, which encodes the 2Cl-/H + exchanger ClC-4, prominently expressed in the hippocampus and cerebellum. Different genotypic variants have been described, each exhibiting specific phenotypic characteristics. The loss-of-function variant p.Gly544Arg in the CLCN4 gene has been described in only two male probands, but there are no reports on phenotypic characterization in females.
METHODS: We present a 30-year-old Italian woman with early-onset drug-resistant epilepsy, developmental and epileptic encephalopathy, developmental delay, absence of verbal language development, behavioral impairment with autistic features, and clusters of seizures during catamenial periods. The interictal EEG showed slight inconstant slowing of the background rhythm, with abnormal frontal predominant mu like rhythm and generalized spike and polyspike wave discharges, which increased in frequency during drowsiness. A brain MRI showed slight cranio-encephalic asymmetry and a smaller size of the left hippocampus. The whole exome sequencing (WES) revealed a de novo heterozygous c.1630G > A variant in the CLCN4 gene, resulting in the amino acid substitution p.Gly544Arg (rs587777161), consistent with Raynaud-Claes syndrome.
CONCLUSIONS: Our patient is the first case of a de novo p.Gly544Arg variant of the CLCN4 gene in a female proband, confirming that female patients with Raynaud-Claes syndrome can be as severely affected as the male counterparts. Our case expands the phenotypic characterization of different genotypic CLCN4 variants, which can become crucial in the future for early diagnosis if targeted therapy becomes available.
METHODS: We present a 30-year-old Italian woman with early-onset drug-resistant epilepsy, developmental and epileptic encephalopathy, developmental delay, absence of verbal language development, behavioral impairment with autistic features, and clusters of seizures during catamenial periods. The interictal EEG showed slight inconstant slowing of the background rhythm, with abnormal frontal predominant mu like rhythm and generalized spike and polyspike wave discharges, which increased in frequency during drowsiness. A brain MRI showed slight cranio-encephalic asymmetry and a smaller size of the left hippocampus. The whole exome sequencing (WES) revealed a de novo heterozygous c.1630G > A variant in the CLCN4 gene, resulting in the amino acid substitution p.Gly544Arg (rs587777161), consistent with Raynaud-Claes syndrome.
CONCLUSIONS: Our patient is the first case of a de novo p.Gly544Arg variant of the CLCN4 gene in a female proband, confirming that female patients with Raynaud-Claes syndrome can be as severely affected as the male counterparts. Our case expands the phenotypic characterization of different genotypic CLCN4 variants, which can become crucial in the future for early diagnosis if targeted therapy becomes available.
摘要：
背景：雷诺-克莱斯综合征是一种非常罕见的X连锁疾病，以智力残疾为特征，语言发育受损，大脑异常,面部畸形和耐药性癫痫。它是由CLCN4基因的功能缺失变异引起的，编码2Cl-/H交换子ClC-4，在海马和小脑中显著表达。已经描述了不同的基因型变异，每个都表现出特定的表型特征。仅在两个男性先证者中描述了CLCN4基因中的功能丧失变体p.Gly544Arg，但是没有关于女性表型特征的报道。
方法：我们介绍了一名30岁的意大利女性，患有早发性抗药性癫痫，发育性和癫痫性脑病，发育迟缓,缺乏口头语言的发展，有自闭症特征的行为障碍，以及月经期间的一系列癫痫发作。发作间脑电图显示背景节律轻微的不恒定减慢，具有异常的额叶占优势的Mu样节律和广义的尖峰和多尖峰波放电，在困倦期间频率增加。脑MRI显示轻微的颅脑不对称性和较小的左海马。全外显子组测序（WES）揭示了CLCN4基因中的从头杂合c.1630G>A变体，导致氨基酸取代p.Gly544Arg（rs587777161），符合雷诺-克莱斯综合征.
结论：我们的患者是女性先证者中首例CLCN4基因的从头p.Gly544Arg变体，确认患有雷诺-克莱斯综合征的女性患者可能与男性患者一样受到严重影响。我们的案例扩展了不同基因型CLCN4变体的表型表征，如果靶向治疗可用，这在未来的早期诊断中可能变得至关重要。
方法：我们介绍了一名30岁的意大利女性，患有早发性抗药性癫痫，发育性和癫痫性脑病，发育迟缓,缺乏口头语言的发展，有自闭症特征的行为障碍，以及月经期间的一系列癫痫发作。发作间脑电图显示背景节律轻微的不恒定减慢，具有异常的额叶占优势的Mu样节律和广义的尖峰和多尖峰波放电，在困倦期间频率增加。脑MRI显示轻微的颅脑不对称性和较小的左海马。全外显子组测序（WES）揭示了CLCN4基因中的从头杂合c.1630G>A变体，导致氨基酸取代p.Gly544Arg（rs587777161），符合雷诺-克莱斯综合征.
结论：我们的患者是女性先证者中首例CLCN4基因的从头p.Gly544Arg变体，确认患有雷诺-克莱斯综合征的女性患者可能与男性患者一样受到严重影响。我们的案例扩展了不同基因型CLCN4变体的表型表征，如果靶向治疗可用，这在未来的早期诊断中可能变得至关重要。
