Abstract：
Dysregulation of RAS or its major effector pathway is the molecular mechanism of RASopathies, a group of multisystemic congenital disorders. Neurologic complications are especially challenging in the management of the rare RASopathy cardiofaciocutaneous (CFC) syndrome. This study evaluated clinical neurologic and neurodevelopmental features and their associations with CFC syndrome gene variants.
A multinational cohort of 138 individuals with CFC syndrome (BRAF = 90, MAP2K1 = 36, MAP2K2 = 10, KRAS = 2) was recruited. Neurologic presentation was captured via clinician review of medical records and caregiver-completed electronic surveys. Validated measures of seizure severity, adaptive function, and gross motor function were obtained.
The overall frequency of intellectual disability and seizures was 82% and 55%, respectively. The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants. A disproportionate incidence of severe, treatment-resistant seizures was observed in patients with variants in the catalytic protein kinase domain of BRAF and at the common p.Y130 site of MAP2K1. Neurodevelopmental outcomes were associated with genotype as well as seizure severity.
Molecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome. Study results identified potential CFC syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment.
A multinational cohort of 138 individuals with CFC syndrome (BRAF = 90, MAP2K1 = 36, MAP2K2 = 10, KRAS = 2) was recruited. Neurologic presentation was captured via clinician review of medical records and caregiver-completed electronic surveys. Validated measures of seizure severity, adaptive function, and gross motor function were obtained.
The overall frequency of intellectual disability and seizures was 82% and 55%, respectively. The frequency and severity of seizures was higher among individuals with BRAF or MAP2K1 variants than in those with MAP2K2 variants. A disproportionate incidence of severe, treatment-resistant seizures was observed in patients with variants in the catalytic protein kinase domain of BRAF and at the common p.Y130 site of MAP2K1. Neurodevelopmental outcomes were associated with genotype as well as seizure severity.
Molecular genetic testing can aid in prediction of epilepsy and neurodevelopmental phenotypes in CFC syndrome. Study results identified potential CFC syndrome-associated variants in the development of relevant animal models for neurologic, neurocognitive, and motor function impairment.
摘要：
RAS或其主要效应途径的失调是RAS的分子机制，一组多系统先天性疾病。神经系统并发症在罕见的先天性心脏病（CFC）综合征的治疗中尤其具有挑战性。这项研究评估了临床神经系统和神经发育特征及其与CFC综合征基因变异的关联。
招募了一个由138名CFC综合征患者组成的跨国队列（BRAF=90，MAP2K1=36，MAP2K2=10，KRAS=2）。通过临床医生对病历的审查和护理人员完成的电子调查来捕获神经系统表现。已验证的癫痫发作严重程度的措施，自适应函数，并获得粗大运动功能。
智力残疾和癫痫发作的总体频率为82％和55％，分别。BRAF或MAP2K1变异个体的癫痫发作频率和严重程度高于MAP2K2变异个体。不成比例的严重发病率，在BRAF催化蛋白激酶结构域和MAP2K1共同p.Y130位点变异的患者中观察到治疗抗性癫痫发作.神经发育结果与基因型以及癫痫发作严重程度相关。
分子遗传学检测有助于预测CFC综合征中的癫痫和神经发育表型。研究结果在相关动物模型的开发中发现了潜在的CFC综合征相关变异，神经认知，和运动功能障碍。
招募了一个由138名CFC综合征患者组成的跨国队列（BRAF=90，MAP2K1=36，MAP2K2=10，KRAS=2）。通过临床医生对病历的审查和护理人员完成的电子调查来捕获神经系统表现。已验证的癫痫发作严重程度的措施，自适应函数，并获得粗大运动功能。
智力残疾和癫痫发作的总体频率为82％和55％，分别。BRAF或MAP2K1变异个体的癫痫发作频率和严重程度高于MAP2K2变异个体。不成比例的严重发病率，在BRAF催化蛋白激酶结构域和MAP2K1共同p.Y130位点变异的患者中观察到治疗抗性癫痫发作.神经发育结果与基因型以及癫痫发作严重程度相关。
分子遗传学检测有助于预测CFC综合征中的癫痫和神经发育表型。研究结果在相关动物模型的开发中发现了潜在的CFC综合征相关变异，神经认知，和运动功能障碍。
