Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients.
Expansion of Clinical and Genetic Spectrum of DDX3X Neurodevelopmental Disorder in 23 Chinese Patients.
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DOI：
10.3389/fnmol.2022.793001
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发表时间：
2022
影响因子：
4.8
通讯作者：
Long L
中科院分区：
文献类型：
--
作者：
Dai Y;Yang Z;Guo J;Li H;Gong J;Xie Y;Xiao B;Wang H;Long L
从头发生的DDX3X变异占女性不明原因智力残疾病例的1-3%，在男性中非常罕见。然而，DDX3X神经发育障碍在中国队列中的临床和遗传特征尚未明确。对2317例不明原因智力残疾（ID）先证进行全外显子组测序（WES），共检测出23例中国患者（女性22例，男性1例）22例新发DDX3X有害变异。收集队列的年龄、性别、遗传资料、喂养情况、生长发育情况及辅助检查。采用中文版Gesell发育诊断量表（GDDS-C）评估DDX3X患者的神经发育。社会沟通问卷(SCQ)-终身版被用作评估自闭症谱系障碍（ASD）风险的主要筛选者。共有17个DDX3X变异是新的，22个是新生的。总的来说，错义变异仅比功能缺失变异略常见，并且主要位于两个功能子域。该队列的平均年龄为2.67（±1.42）岁。该队列与先前报道的重叠表型谱包括不同程度的智力障碍（23/ 23,100%），肌肉张力异常（17/ 23,73.9%），进食困难（13/ 23,56.5%），眼科问题（11/ 23,47.8%）和癫痫发作（6/ 23,26.1%）。15例患者有明显的脑解剖破坏（15/23,65.2%），包括侧脑室增大、胼胝体异常和髓鞘形成延迟。脑电图异常9例（9/23,39.1%）。甲状腺功能减退首先被认为是一种新的临床特征（6/ 23,26.1%）。21例患者GDDS-C的5个主要神经发育域严重受损，13例患者高于ASD的“高危”阈值。尽管与先前报道的队列有一定程度的表型重叠，但我们的研究描述了中国人群中另外23名携带DDX3X变异的个体的表型和变异谱，并将甲状腺功能减退症作为一项新发现。我们证实了DDX3X在不明原因智力残疾中作为致病基因的重要性，支持了WES在不明原因智力残疾患者中应用的必要性。
De novo DDX3X variants account for 1–3% of unexplained intellectual disability cases in females and very rarely in males. Yet, the clinical and genetic features of DDX3X 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 de novo DDX3X 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 DDX3X 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 DDX3X variants were novel and 22 were de novo. 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 DDX3X variants in the Chinese population, adding hypothyroidism as a novel finding. We confirmed the importance of DDX3X as a pathogenic gene in unexplained intellectual disability, supporting the necessity of the application of WES in patients with unexplained intellectual disability.
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