Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus.
Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus.
复制标题
DDX53 的遗传变异导致与 Xp22.11 基因座相关的自闭症谱系障碍。
DOI：
10.1101/2023.12.21.23300383
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Brusco,Alfredo
中科院分区：
文献类型：
--
作者：
Scala,Marcello;Bradley,ClarrisaA;Howe,JenniferL;Trost,Brett;Salazar,NelsonBautista;Shum,Carole;Reuter,MiriamS;MacDonald,JeffreyR;Ko,SangyoonY;Frankland,PaulW;Granger,Leslie;Anadiotis,George;Pullano,Verdiana;Brusco,Alfredo
自闭症谱系障碍表现出∼4：1的男女性别偏见，其特征是早期起病的社交/沟通技能障碍、兴趣受限和刻板印象行为。Xp22.11基因座的突变与男性ASD有关。该基因座包括三个外显子PTCHD_1，一个相邻的多异构体长非编码核糖核酸，命名为PTCHD_1-AS(跨越∼1 Mb)，以及一个功能不佳的单外显子解旋酶DDX53，它是PTCHD_1-AS的内含子。虽然PTCHD/PTCHD-AS与ASD的关系正在研究中，但DDX53的作用还没有得到全面的研究，部分原因是没有明显的小鼠功能同源基因。通过临床测试，我们从8个无关的家系中鉴定出8名男性和2名女性患有ASD，这些家系携带DDX53罕见的、预测的损害或功能丧失变异。此外，我们发现了一个由一名男性先证者及其患上高功能自闭症的母亲组成的家庭，两人都含有涉及非编码RNAPTCHD1-AS的DDX53和外显子的基因缺失。然后，我们检查了数据库，包括自闭症演讲MSSNG和西蒙斯基金会自闭症研究倡议，以及人口控制。我们确认了另外26名ASD患者，他们有19个主要是母系遗传的、罕见的破坏性DDX53变异，包括从最初的临床分析中在家系中检测到的两个变异。我们在人类中的发现支持DDX53和ASD之间的直接联系，这在临床基因测试中将是重要的。这些与自闭症相关的发现，再加上在小鼠身上没有发现功能性同源基因的观察，也可能影响ASD小鼠模型的设计和解释。
Autism spectrum disorder (ASD) exhibits an ∼4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exonPTCHD1, an adjacent multi-isoform long noncoding RNA (lncRNA) namedPTCHD1-AS(spanning ∼1 Mb), and a poorly characterized single-exon RNA helicase namedDDX53that is intronic toPTCHD1-AS. While the relationship betweenPTCHD1/PTCHD1-ASand ASD is being studied, the role ofDDX53has not been comprehensively examined, in part because there is no apparent functional murine ortholog. Through clinical testing, here, we identified 8 males and 2 females with ASD from 8 unrelated families carrying rare, predicted damaging or loss-of-function variants inDDX53. Additionally, we identified a family consisting of a male proband and his affected mother with high-functioning autism, both harboring a gene deletion involvingDDX53and exons of the noncoding RNAPTCHD1-AS. Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 26 additional individuals with ASD harboring 19 mostly maternally inherited, rare, damagingDDX53variations, including two variants detected in families from the original clinical analysis. Our findings in humans support a direct link betweenDDX53and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mice, may also influence the design and interpretation of murine modeling of ASD.