Abstract
The prevalence of autism spectrum disorder (ASD) is high, yet the etiology of this disorder is still uncertain. Advancements in genetic analysis have provided the ability to identify potential genetic changes that may contribute to ASD. Interestingly, several genetic syndromes have been linked to metabolic dysfunction, suggesting an avenue for treatment. In this case study, we report siblings with ASD who had similar initial phenotypic presentations. Whole exome sequencing (WES) revealed a novel c.795delT mutation in the WDR45 gene affecting the girl, which was consistent with her eventual progression to a Rett-like syndrome phenotype including seizures along with a stereotypical cyclic breathing pattern. Interestingly, WES identified that the brother harbored a novel heterozygous Y1546H variant in the DEP domain-containing protein 5 (DEPDC5) gene, consistent with his presentation. Both siblings underwent a metabolic workup that demonstrated different patterns of mitochondrial dysfunction. The girl demonstrated statistically significant elevations in mitochondrial activity of complex I + III in both muscle and fibroblasts and increased respiration in peripheral blood mononuclear cells (PBMCs) on Seahorse Extracellular Flux analysis. The boy demonstrates a statistically significant decrease in complex IV activity in buccal epithelium and decreased respiration in PBMCs. These cases highlight the differences in genetic abnormalities even in siblings with ASD phenotypes as well as highlights the individual role of novel mutations in the WDR45 and DEPDC5 genes. These cases demonstrate the importance of advanced genetic testing combined with metabolic evaluations in the workup of children with ASD.
Highlights
Autism spectrum disorder (ASD) is a behaviorally defined disorder characterized by social communication deficits along with restricted interests and repetitive behaviors, which affects nearly 2% of children [1]
Mitochondrial dysfunction is believed to be important in autism spectrum disorder (ASD) as biomarkers of mitochondrial dysfunction in children with ASD are correlated with ASD severity [30, 31] and, recently, we demonstrated that abnormal mitochondrial function was related to worse repetitive and stereotypical behavior in a cell line sibling study of ASD [32]
We report on a female and a male set of siblings with ASD who were referred to our clinic for a comprehensive medical assessment
Summary
Autism spectrum disorder (ASD) is a behaviorally defined disorder characterized by social communication deficits along with restricted interests and repetitive behaviors, which affects nearly 2% of children [1]. Novel WDR45 and DEPDC5 Mutations in Autism genetic factors contribute about [2] and several predisposing factors such as paternal age, prematurity, prenatal folate, and endocrine abnormalities influence the risk of developing ASD [3]. The persistent concentration on genetic causes of ASD [4] is fueled by the high recurrent risk of ASD in siblings and the association of ASD with well-defined genetic syndromes, such as Down and Turner [5]. About 10% ASD cases demonstrate de novo or inherited copy number variations, such as microdeletion or microduplication syndromes [5,6,7,8]. The remaining single-gene defects are attributed to rare genetic disorders such as Rett syndrome, tuberous sclerosis, and PTEN syndrome [5]
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