Abstract：
OBJECTIVE: To delineate the comprehensive phenotypic spectrum of SYNGAP1-related disorder in a large patient cohort aggregated through a digital registry.
METHODS: We obtained de-identified patient data from an online registry. Data were extracted from uploaded medical records. We reclassified all SYNGAP1 variants using American College of Medical Genetics criteria and included patients with pathogenic/likely pathogenic (P/LP) single nucleotide variants or microdeletions incorporating SYNGAP1. We analyzed neurodevelopmental phenotypes, including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), behavioral disorders, and gait dysfunction for all patients with respect to variant type and location within the SynGAP1 protein.
RESULTS: We identified 147 patients (50% male, median age 8 years) with P/LP SYNGAP1 variants from 151 individuals with data available through the database. One hundred nine were truncating variants and 22 were missense. All patients were diagnosed with global developmental delay (GDD) and/or ID, and 123 patients (84%) were diagnosed with epilepsy. Of those with epilepsy, 73% of patients had GDD diagnosed before epilepsy was diagnosed. Other prominent features included autistic traits (n = 100, 68%), behavioral problems (n = 100, 68%), sleep problems (n = 90, 61%), anxiety (n = 35, 24%), ataxia or abnormal gait (n = 69, 47%), sensory problems (n = 32, 22%), and feeding difficulties (n = 69, 47%). Behavioral problems were more likely in those patients diagnosed with anxiety (odds ratio [OR] 3.6, p = .014) and sleep problems (OR 2.41, p = .015) but not necessarily those with autistic traits. Patients with variants in exons 1-4 were more likely to have the ability to speak in phrases vs those with variants in exons 5-19, and epilepsy occurred less frequently in patients with variants in the SH3 binding motif.
CONCLUSIONS: We demonstrate that the data obtained from a digital registry recapitulate earlier but smaller studies of SYNGAP1-related disorder and add additional genotype-phenotype relationships, validating the use of the digital registry. Access to data through digital registries broadens the possibilities for efficient data collection in rare diseases.
METHODS: We obtained de-identified patient data from an online registry. Data were extracted from uploaded medical records. We reclassified all SYNGAP1 variants using American College of Medical Genetics criteria and included patients with pathogenic/likely pathogenic (P/LP) single nucleotide variants or microdeletions incorporating SYNGAP1. We analyzed neurodevelopmental phenotypes, including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), behavioral disorders, and gait dysfunction for all patients with respect to variant type and location within the SynGAP1 protein.
RESULTS: We identified 147 patients (50% male, median age 8 years) with P/LP SYNGAP1 variants from 151 individuals with data available through the database. One hundred nine were truncating variants and 22 were missense. All patients were diagnosed with global developmental delay (GDD) and/or ID, and 123 patients (84%) were diagnosed with epilepsy. Of those with epilepsy, 73% of patients had GDD diagnosed before epilepsy was diagnosed. Other prominent features included autistic traits (n = 100, 68%), behavioral problems (n = 100, 68%), sleep problems (n = 90, 61%), anxiety (n = 35, 24%), ataxia or abnormal gait (n = 69, 47%), sensory problems (n = 32, 22%), and feeding difficulties (n = 69, 47%). Behavioral problems were more likely in those patients diagnosed with anxiety (odds ratio [OR] 3.6, p = .014) and sleep problems (OR 2.41, p = .015) but not necessarily those with autistic traits. Patients with variants in exons 1-4 were more likely to have the ability to speak in phrases vs those with variants in exons 5-19, and epilepsy occurred less frequently in patients with variants in the SH3 binding motif.
CONCLUSIONS: We demonstrate that the data obtained from a digital registry recapitulate earlier but smaller studies of SYNGAP1-related disorder and add additional genotype-phenotype relationships, validating the use of the digital registry. Access to data through digital registries broadens the possibilities for efficient data collection in rare diseases.
摘要：
目的：在通过数字注册汇总的大型患者队列中描绘SYNGAP1相关疾病的综合表型谱。
方法：我们从在线注册表中获得了去识别的患者数据。从上传的医疗记录中提取数据。我们使用美国医学遗传学学院标准对所有SYNGAP1变异进行了重新分类，并纳入了具有致病性/可能致病性（P/LP）单核苷酸变异或微缺失掺入SYNGAP1的患者。我们分析了神经发育表型,包括癫痫,智力残疾（ID），自闭症谱系障碍（ASD），行为障碍,在SynGAP1蛋白的变异类型和位置方面，所有患者的步态功能障碍。
结果：我们确定了147例患者（50％为男性，中位年龄8岁），来自151名个体的P/LPSYNGAP1变异，数据可通过数据库获得。109个是截断变体，22个是错义。所有患者均被诊断为整体发育迟缓（GDD）和/或ID，123例患者（84%）被诊断为癫痫。在那些患有癫痫的人中，73%的患者在诊断癫痫之前就诊断出了GDD。其他突出特征包括自闭症特征(n=100，68%)，行为问题(n=100，68%)，睡眠问题（n=90，61%），焦虑（n=35，24%），共济失调或步态异常（n=69，47％），感觉问题(n=32，22%)，和喂养困难(n=69，47%)。在那些被诊断为焦虑（比值比[OR]3.6，p=.014）和睡眠问题（OR2.41，p=.015）的患者中，行为问题更可能发生，但不一定具有自闭症特征的患者。外显子1-4变异的患者比外显子5-19变异的患者更有可能用短语说话，并且在SH3结合基序变异的患者中癫痫的发生率较低。
结论：我们证明，从数字注册获得的数据概括了早期但较小的SYNGAP1相关疾病的研究，并增加了其他基因型-表型关系，验证数字注册表的使用。通过数字登记处访问数据扩大了有效收集罕见疾病数据的可能性。
方法：我们从在线注册表中获得了去识别的患者数据。从上传的医疗记录中提取数据。我们使用美国医学遗传学学院标准对所有SYNGAP1变异进行了重新分类，并纳入了具有致病性/可能致病性（P/LP）单核苷酸变异或微缺失掺入SYNGAP1的患者。我们分析了神经发育表型,包括癫痫,智力残疾（ID），自闭症谱系障碍（ASD），行为障碍,在SynGAP1蛋白的变异类型和位置方面，所有患者的步态功能障碍。
结果：我们确定了147例患者（50％为男性，中位年龄8岁），来自151名个体的P/LPSYNGAP1变异，数据可通过数据库获得。109个是截断变体，22个是错义。所有患者均被诊断为整体发育迟缓（GDD）和/或ID，123例患者（84%）被诊断为癫痫。在那些患有癫痫的人中，73%的患者在诊断癫痫之前就诊断出了GDD。其他突出特征包括自闭症特征(n=100，68%)，行为问题(n=100，68%)，睡眠问题（n=90，61%），焦虑（n=35，24%），共济失调或步态异常（n=69，47％），感觉问题(n=32，22%)，和喂养困难(n=69，47%)。在那些被诊断为焦虑（比值比[OR]3.6，p=.014）和睡眠问题（OR2.41，p=.015）的患者中，行为问题更可能发生，但不一定具有自闭症特征的患者。外显子1-4变异的患者比外显子5-19变异的患者更有可能用短语说话，并且在SH3结合基序变异的患者中癫痫的发生率较低。
结论：我们证明，从数字注册获得的数据概括了早期但较小的SYNGAP1相关疾病的研究，并增加了其他基因型-表型关系，验证数字注册表的使用。通过数字登记处访问数据扩大了有效收集罕见疾病数据的可能性。
