Gupta Abha R, Westphal Alexander, Yang Daniel Y J, Sullivan Catherine A W, Eilbott Jeffrey, Zaidi Samir, Voos Avery, Vander Wyk Brent C, Ventola Pam, Waqar Zainulabedin, Fernandez Thomas V, Ercan-Sencicek A Gulhan, Walker Michael F, Choi Murim, Schneider Allison, Hedderly Tammy, Baird Gillian, Friedman Hannah, Cordeaux Cara, Ristow Alexandra, Shic Frederick, Volkmar Fred R, Pelphrey Kevin A
Department of Pediatrics, Yale School of Medicine, New Haven, Connecticut USA.
Child Study Center, Yale School of Medicine, New Haven, Connecticut USA.
Mol Autism. 2017 Apr 4;8:19. doi: 10.1186/s13229-017-0133-0. eCollection 2017.
Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences.
We pursued a multidisciplinary study of CDD ( = 17) and three comparison groups: low-functioning ASD ( = 12), high-functioning ASD ( = 50), and typically developing ( = 26) individuals. We performed whole-exome sequencing (WES), copy number variant (CNV), and gene expression analyses of CDD and, on subsets of each cohort, non-sedated functional magnetic resonance imaging (fMRI) while viewing socioemotional (faces) and non-socioemotional (houses) stimuli and eye tracking while viewing emotional faces.
We observed potential differences between CDD and other forms of ASD. WES and CNV analyses identified one or more rare de novo, homozygous, and/or hemizygous (mother-to-son transmission on chrX) variants for most probands that were not shared by unaffected sibling controls. There were no clearly deleterious variants or highly recurrent candidate genes. Candidate genes that were found to be most conserved at variant position and most intolerant of variation, such as , , and , play a role or may be involved in transcription. Using the human BrainSpan transcriptome dataset, CDD candidate genes were found to be more highly expressed in non-neocortical regions than neocortical regions. This expression profile was similar to that of an independent cohort of ASD probands with regression. The non-neocortical regions overlapped with those identified by fMRI as abnormally hyperactive in response to viewing faces, such as the thalamus, cerebellum, caudate, and hippocampus. Eye-tracking analysis showed that, among individuals with ASD, subjects with CDD focused on eyes the most when shown pictures of faces.
Given that cohort sizes were limited by the rarity of CDD, and the challenges of conducting non-sedated fMRI and eye tracking in subjects with ASD and significant ID, this is an exploratory study designed to investigate the neurobiological features of CDD. In addition to reporting the first multimodal analysis of CDD, a combination of fMRI and eye-tracking analyses are being presented for the first time for low-functioning individuals with ASD. Our results suggest differences between CDD and other forms of ASD on the neurobiological as well as clinical level.
儿童退行性精神障碍（CDD）是一种病因不明的罕见自闭症谱系障碍（ASD）形式。其特征为起病较晚出现退化，导致严重智力残疾（ID）和重度自闭症。尽管CDD与其他形式的ASD存在表型差异，但尚不清楚是否存在神经生物学差异。
我们对17例CDD患者以及三个对照组进行了多学科研究：低功能ASD患者（12例）、高功能ASD患者（50例）和发育正常个体（26例）。我们对CDD患者进行了全外显子组测序（WES）、拷贝数变异（CNV）和基因表达分析，并在每个队列的亚组中，在观看社会情感（面部）和非社会情感（房屋）刺激时进行非镇静功能磁共振成像（fMRI），以及在观看情感面部时进行眼动追踪。
我们观察到CDD与其他形式的ASD之间存在潜在差异。WES和CNV分析在大多数先证者中鉴定出一个或多个罕见的新生、纯合和/或半合子（chrX上的母传子）变异，未受影响的同胞对照未共享这些变异。没有明显有害的变异或高度复发的候选基因。在变异位置最保守且对变异最不耐受的候选基因，如[具体基因名称未给出]、[具体基因名称未给出]和[具体基因名称未给出]，发挥作用或可能参与转录。使用人类BrainSpan转录组数据集，发现CDD候选基因在非新皮质区域的表达高于新皮质区域。这种表达谱与一组有退化现象的ASD先证者独立队列相似。非新皮质区域与fMRI确定的在观看面部时异常活跃的区域重叠，如丘脑、小脑、尾状核和海马体。眼动追踪分析表明，在ASD个体中，CDD患者在观看面部图片时最关注眼睛。
鉴于CDD的罕见性限制了队列规模，以及在ASD和严重ID患者中进行非镇静fMRI和眼动追踪的挑战，这是一项旨在研究CDD神经生物学特征的探索性研究。除了报告首次对CDD进行的多模态分析外，还首次为低功能ASD个体呈现了fMRI和眼动追踪分析的组合。我们的结果表明，CDD与其他形式的ASD在神经生物学以及临床水平上存在差异。
