Clothier Jeffery L, Grooms Amy N, Porter-Gill Patricia A, Gill Pritmohinder S, Schaefer G Bradley
Psychiatric Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Arkansas Children's Research Institute, Little Rock, AR 72202, USA.
J Pers Med. 2022 May 27;12(6):886. doi: 10.3390/jpm12060886.
Autism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders and occurs in all racial, ethnic, and socioeconomic groups. Cutting-edge technologies are contributing to understanding genetic underpinnings in ASD. The reported patient is a 32-year-old male and as an infant was noted to have microcephaly, hypospadias, pulmonary vascular anomaly, and small stature. He was diagnosed with Cornelia De Lange Syndrome (CDLS) at that time based on the clinical features. As a child, he had autistic features and intellectual disabilities and as diagnoses with autism and intellectual disability. He was referred as an adult to our neurodiversity clinic and a full exome trio sequencing with reflex to mitochondrial genes identified a de novo variant of uncertain significance in a candidate gene, DCAF1. The specific variant was c.137 C > T (p.Thr46Ile) in exon 4 in the DCAF1 gene. In silico analysis supports a deleterious effect on protein structure/function. DCAF1 participates with DDB1 and CUL4 as a part of the E3 ubiquitin ligase complex. The E3 ligase complex has been associated with a syndromic form of X-linked intellectual disability. The DDB1/CUL4 E3 ubiquitination complex plays a role in methylation-dependent ubiquitination. Next, a methylation study identified a signature similar to the methylation pattern found in X- linked intellectual disability type 93. This is associated with variants of the BRWD3 gene, which is linked with the functioning of the DDB1/CUL4 E3 ubiquitination complex. Taken together, this suggests that the de novo DCAF1 variant may be a newly identified molecular cause of autism and intellectual disability.
自闭症谱系障碍（ASD）是一组异质性神经发育障碍，在所有种族、民族和社会经济群体中均有发生。前沿技术有助于理解ASD的遗传基础。报告的患者为一名32岁男性，婴儿期即被发现有小头畸形、尿道下裂、肺血管异常和身材矮小。当时根据临床特征诊断为科妮莉亚·德朗热综合征（CDLS）。儿童时期，他有自闭症特征和智力残疾，被诊断为自闭症和智力残疾。成年后他被转诊至我们的神经多样性诊所，进行了全外显子三联体测序并对线粒体基因进行了追溯分析，在一个候选基因DCAF1中发现了一个意义未明的新发变异。该特定变异为DCAF1基因第4外显子中的c.137 C>T（p.Thr46Ile）。计算机分析支持该变异对蛋白质结构/功能有有害影响。DCAF1与DDB1和CUL4一起作为E3泛素连接酶复合物的一部分发挥作用。该E3连接酶复合物与一种X连锁智力残疾的综合征形式有关。DDB1/CUL4 E3泛素化复合物在甲基化依赖性泛素化中起作用。接下来，一项甲基化研究发现了一种与93型X连锁智力残疾中发现的甲基化模式相似的特征。这与BRWD3基因的变异有关，而BRWD3基因与DDB1/CUL4 E3泛素化复合物的功能有关。综上所述，这表明新发的DCAF1变异可能是自闭症和智力残疾新发现的分子病因。
