Department of Neurology, Division of Child Neurology, Columbia University Irving Medical Center, New York, NY, USA.
Simons Foundation, New York, NY, USA.
J Neurodev Disord. 2022 Jun 28;14(1):40. doi: 10.1186/s11689-022-09449-7.
SLC6A1-related disorder is a recently identified, rare, genetic neurodevelopmental disorder that is associated with loss-of-function variants in SLC6A1. This gene encodes GABA transporter type I that is responsible for re-uptake of GABA from the synapse into the pre-synaptic terminal or circulating neuroglia. Based upon retrospective review of published cases and available research databases including Epi25 collective and SLC6A1 Connect patient database, the phenotypic spectrum is broad and includes developmental delay, epilepsy, and autism or autistic traits. SLC6A1 is one of the genes included in the Simons Searchlight registry, which includes standardized data collection across genetically identified neurodevelopmental conditions.
In this study, we compare parent-report measures of phenotypic features in the Simons Searchlight registry to previously published, provider-reported cases to assess if parent-report measures are consistent with what has been reported in the literature.
There were 116 participants in the provider-reported dataset compared to 43 individuals in the caregiver-reported dataset. Carriers in Searchlight had 83 unique pathogenic or likely pathogenic variants in SLC6A1, which were predominantly missense or nonsense variants. There was no significant difference between groups for the prevalence of developmental delay, ASD, or ADHD. Caregivers more often reported hypotonia, while epilepsy was slightly more frequently reported by providers.
We propose that standardized parent-report data collection methods are consistent with provider reports on many core features of SLC6A1-related disorder. The availability of patient registries and standardized natural history studies may fill an important need in clinical trial readiness programs, with larger sample sizes than smaller published case series.
SLC6A1 相关障碍是一种最近发现的罕见遗传性神经发育障碍，与 SLC6A1 的功能丧失变异有关。该基因编码 GABA 转运体 I，负责将 GABA 从突触重新摄取到突触前末端或循环神经胶质中。基于对已发表病例和包括 Epi25 集合和 SLC6A1 Connect 患者数据库在内的可用研究数据库的回顾性审查，表型谱广泛，包括发育迟缓、癫痫、自闭症或自闭症特征。SLC6A1 是 Simons Searchlight 注册中心包含的基因之一，该注册中心包括对遗传确定的神经发育状况进行标准化数据收集。
在这项研究中，我们将 Simons Searchlight 注册中心的家长报告特征与以前发表的、提供者报告的病例进行比较，以评估家长报告的测量是否与文献中的报道一致。
提供者报告数据集有 116 名参与者，而照顾者报告数据集有 43 名参与者。Searchlight 中的携带者在 SLC6A1 中具有 83 个独特的致病性或可能致病性变体，这些变体主要是错义或无义变体。两组在发育迟缓、ASD 或 ADHD 的患病率方面没有显著差异。照顾者更常报告张力减退，而癫痫则更常由提供者报告。
我们提出，标准化的家长报告数据收集方法与 SLC6A1 相关障碍的提供者报告在许多核心特征上是一致的。患者登记处和标准化自然史研究的可用性可能满足临床试验准备计划的重要需求，其样本量大于较小的已发表病例系列。
