Behavioural and Brain Sciences Unit, Population, Policy and Practice Department, University College London (UCL) Great Ormond Street Institute for Child Health, 30 Guilford Street, London, WC1N 1EH, UK.
J Neurodev Disord. 2024 Aug 15;16(1):46. doi: 10.1186/s11689-024-09563-8.
SYNGAP1 variants are associated with varying degrees of intellectual disability (ID), developmental delay (DD), epilepsy, autism, and behavioural difficulties. These features may also be observed in other monogenic conditions. There is a need to systematically compare the characteristics of SYNGAP1 with other monogenic causes of ID and DD to identify features unique to the SYNAGP1 phenotype. We aimed to contrast the neurodevelopmental and behavioural phenotype of children with SYNGAP1-related ID (SYNGAP1-ID) to children with other monogenic conditions and a matched degree of ID.
Participants were identified from the IMAGINE-ID study, a UK-based, national cohort study of neuropsychiatric risk in children with ID of known genetic origin. Thirteen children with SYNGAP1 variants (age 4-16 years; 85% female) were matched (2:1) with 26 controls with other monogenic causes of ID for chronological and mental age, sex, socio-economic deprivation, adaptive behaviour, and physical health difficulties. Caregivers completed the Development and Wellbeing Assessment (DAWBA) and physical health questionnaires.
Our results demonstrate that seizures affected children with SYNGAP1-ID (84.6%) more frequently than the ID-comparison group (7.6%; p = < 0.001). Fine-motor development was disproportionally impaired in SYNGAP1-ID, with 92.3% of children experiencing difficulties compared to 50% of ID-comparisons(p = 0.03). Gross motor and social development did not differ between the two groups. Children with SYNGAP1-ID were more likely to be non-verbal (61.5%) than ID-comparisons (23.1%; p = 0.01). Those children able to speak, spoke their first words at the same age as the ID-comparison group (mean = 3.25 years), yet achieved lower language competency (p = 0.04). Children with SYNGAP1-ID compared to the ID-comparison group were not more likely to meet criteria for autism (SYNGAP1-ID = 46.2%; ID-comparison = 30.7%; p = .35), attention-deficit hyperactivity disorder (15.4%;15.4%; p = 1), generalised anxiety (7.7%;15.4%; p = .49) or oppositional defiant disorder (7.7%;0%; p = .15).
For the first time, we demonstrate that SYNGAP1-ID is associated with fine motor and language difficulties beyond those experienced by children with other genetic causes of DD and ID. Targeted occupational and speech and language therapies should be incorporated early into SYNGAP1-ID management.
SYNGAP1 变异与不同程度的智力障碍（ID）、发育迟缓（DD）、癫痫、自闭症和行为困难有关。这些特征也可能在其他单基因疾病中观察到。需要系统比较 SYNGAP1 与其他导致 ID 和 DD 的单基因病因的特征，以确定 SYNAGP1 表型特有的特征。我们旨在对比 SYNGAP1 相关 ID（SYNGAP1-ID）患儿与其他单基因疾病和匹配 ID 患儿的神经发育和行为表型。
参与者是从英国基于 IMAGINE-ID 研究中确定的，该研究是一项针对具有已知遗传来源 ID 的儿童的神经精神风险的全国性队列研究。13 名患有 SYNGAP1 变异的儿童（年龄 4-16 岁；85%为女性）与 26 名患有其他单基因病因 ID 的儿童按年龄和智力年龄、性别、社会经济剥夺、适应行为和身体健康困难进行 2:1 匹配。照顾者完成了发育和健康评估（DAWBA）和身体健康问卷。
我们的结果表明，癫痫影响 SYNGAP1-ID 患儿（84.6%）的频率高于 ID 对照组（7.6%；p<0.001）。精细运动发育在 SYNGAP1-ID 中不成比例地受损，92.3%的儿童有困难，而 ID 对照组为 50%（p=0.03）。两组的粗大运动和社会发育没有差异。SYNGAP1-ID 患儿更有可能是非语言的（61.5%），而 ID 对照组为 23.1%（p=0.01）。那些能够说话的孩子与 ID 对照组的孩子一样，在相同的年龄说出了他们的第一个单词（平均=3.25 岁），但语言能力较低（p=0.04）。与 ID 对照组相比，SYNGAP1-ID 患儿更不可能符合自闭症（SYNGAP1-ID=46.2%；ID 对照组=30.7%；p=0.35）、注意缺陷多动障碍（15.4%；15.4%；p=1）、广泛性焦虑症（7.7%；15.4%；p=0.49）或对立违抗障碍（7.7%；0%；p=0.15）的标准。
我们首次证明，SYNGAP1-ID 除了与其他遗传原因导致的 DD 和 ID 患儿的精细运动和语言困难有关外，还与这些困难有关。针对特定的职业和言语语言治疗应该在 SYNGAP1-ID 管理中尽早纳入。
