Dai Yuwei, Yang Zhuanyi, Guo Jialing, Li Haoyu, Gong Jiaoe, Xie Yuanyuan, Xiao Bo, Wang Hua, Long Lili
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
Front Mol Neurosci. 2022 Mar 22;15:793001. doi: 10.3389/fnmol.2022.793001. eCollection 2022.
variants account for 1-3% of unexplained intellectual disability cases in females and very rarely in males. Yet, the clinical and genetic features of neurodevelopmental disorder in the Chinese cohort have not been characterized.
A total of 23 Chinese patients (i.e., 22 female and 1 male) with 22 deleterious variants were detected among 2,317 probands with unexplained intellectual disability (ID) undertaking whole exome sequencing (WES). The age, sex, genetic data, feeding situation, growth, developmental conditions, and auxiliary examinations of the cohort were collected. The Chinese version of the Gesell Development Diagnosis Scale (GDDS-C) was used to evaluate neurodevelopment of patients. The Social Communication Questionnaire (SCQ)-Lifetime version was applied as a primary screener to assess risk for autism spectrum disorder (ASD).
A total of 17 variants were novel and 22 were . Missense variants overall were only slightly more common than loss-of-function variants and were mainly located in two functional subdomains. The average age of this cohort was 2.67 (±1.42) years old. The overlapping phenotypic spectrum between this cohort and previously described reports includes intellectual disability (23/23, 100%) with varying degrees of severity, muscle tone abnormalities (17/23, 73.9%), feeding difficulties (13/23, 56.5%), ophthalmologic problems (11/23, 47.8%), and seizures (6/23, 26.1%). A total of 15 individuals had notable brain anatomical disruption (15/23, 65.2%), including lateral ventricle enlargement, corpus callosum abnormalities, and delayed myelination. Furthermore, 9 patients showed abnormal electroencephalogram results (9/23, 39.1%). Hypothyroidism was first noted as a novel clinical feature (6/23, 26.1%). The five primary neurodevelopmental domains of GDDS-C in 21 patients were impaired severely, and 13 individuals were above the "at-risk" threshold for ASD.
Although a certain degree of phenotypic overlap with previously reported cohorts, our study described the phenotypic and variation spectrum of 23 additional individuals carrying variants in the Chinese population, adding hypothyroidism as a novel finding. We confirmed the importance of as a pathogenic gene in unexplained intellectual disability, supporting the necessity of the application of WES in patients with unexplained intellectual disability.
该变异在女性不明原因智力残疾病例中占1%-3%，在男性中极为罕见。然而，中国人群中神经发育障碍的临床和遗传特征尚未得到描述。
在2317例进行全外显子测序（WES）的不明原因智力残疾（ID）先证者中，共检测出23例中国患者（即22例女性和1例男性）携带22种有害变异。收集了该队列的年龄、性别、遗传数据、喂养情况、生长发育状况及辅助检查结果。使用中文版格塞尔发育诊断量表（GDDS-C）评估患者的神经发育情况。应用社交沟通问卷（SCQ）终身版作为主要筛查工具评估自闭症谱系障碍（ASD）风险。
共17种变异为新发现，22种变异……错义变异总体上仅略比功能丧失变异更常见，且主要位于两个功能亚域。该队列的平均年龄为2.67（±1.42）岁。该队列与先前报道的病例在表型谱上的重叠包括不同严重程度的智力残疾（23/23，100%）、肌张力异常（17/23，73.9%）、喂养困难（13/23，56.5%）、眼科问题（11/23，47.8%）和癫痫发作（6/23，26.1%）。共有15例个体存在明显的脑解剖结构破坏（15/23，65.2%），包括侧脑室扩大、胼胝体异常和髓鞘形成延迟。此外，9例患者脑电图结果异常（9/23，39.1%）。甲状腺功能减退首次被发现是一种新的临床特征（6/23，26.1%）。21例患者的GDDS-C五个主要神经发育领域严重受损，13例个体高于ASD的“风险”阈值。
尽管与先前报道的队列存在一定程度的表型重叠，但我们研究描述了中国人群中另外23例携带变异个体的表型和变异谱，新增甲状腺功能减退这一新发现。我们证实了……作为不明原因智力残疾致病基因的重要性，支持了对不明原因智力残疾患者应用WES的必要性。
