Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, Box 1230, New York, NY, 10029, USA.
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Mol Autism. 2021 May 16;12(1):36. doi: 10.1186/s13229-021-00431-z.
DDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored.
We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions.
Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants.
Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder.
This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes.
DDX3X 综合征是一种新发现的遗传疾病，占女性不明原因发育迟缓及/或智力障碍（ID）的 1-3%，与运动和语言延迟以及自闭症谱系障碍（ASD）有关。迄今为止，该综合征的已发表表型特征主要依赖于病历回顾；此外，该综合征的行为维度尚未得到充分探索。
我们对 14 名女性和 1 名男性进行了为期数天的前瞻性详细表型分析，重点是行为、心理和神经测量。该队列中的 3 名参与者以前的表型信息有限，并在此项研究中重新进行了评估。我们将结果与人群正常值进行比较，并对携带（1）蛋白截断变异体或（2）错义变异体或框内缺失的个体进行表型比较。
80%的个体符合 ID 标准，60%符合 ASD 标准，53%符合注意缺陷多动障碍（ADHD）标准。运动和语言延迟很常见，感觉处理异常也很常见。该队列包括 5 个错义变异体、3 个内含子/剪接位点变异体、2 个无义变异体、2 个移码变异体、2 个框内缺失和 1 个起始密码子变异体。基因型-表型相关性表明，平均而言，与蛋白截断变异体相比，错义变异体/框内缺失与更严重的语言、运动和适应能力缺陷相关。
样本量适中，但 DDX3X 综合征是一种罕见且诊断不足的疾病。
本研究首次对 DDX3X 综合征进行了前瞻性详细的表型特征描述，扩展了我们对神经行为表型的理解。金标准诊断方法显示 ID、ASD 和 ADHD 的发病率较高。此外，还观察到感觉缺陷是该综合征的一个关键部分。即使样本量适中，我们也观察到与错义变异体/框内缺失相关的基因型-表型相关性的证据，通常与更严重的表型相关。
