De novo mutations within metabolism networks of amino acid/protein/energy in autistic children with intellectual disability

Autism spectrum disorder (ASD) is often accompanied by many mental problems, such as intelligent deficits. Despite extensive studies, however, the genetic basis for this comorbidity is still not clear. In this study, we conducted whole exome sequencing (WES) in 79 ASD children together with their parents (trios). We identified 89 de novo mutant genes, of which 34 genes were previously reported to be associated with ASD, including double hits in the EGF repeats of NOTCH1 gene (p.V999M and p.S1027L). Interestingly, among these 34 genes, 22 ones may directly affect intelligence quotient (IQ). Further analyses revealed that those IQ-related genes were enriched in protein synthesis, energy metabolism, and amino acid metabolism, and at least 9 genes (CACNA1A, ALG9, PALM2, MGAT4A, PCK2, PLEKHA1, PSME3, ADI1 and TLE3) were involved in above pathways. Seven patients who harbored these gene mutations showed a high prevalence of a low IQ score (<70), a non-verbal language, and an early diagnostic age (<4 years). Furthermore, our panel of these 9 genes reached a 10.2% diagnostic rate (5/49) in early diagnostic patients with a low IQ score, and also reached a 10% diagnostic yield in those with both a low IQ score and a non-verbal language (4/40). We found some new genetic disposition for ASD accompanying with intellectual disability in this study. Our results are helpful for etiologic research and early diagnoses of intellectual disability in ASD. Larger population studies and further mechanism studies are warranted.
Keywords: Autism, Gene Mutation; Comorbidity; Intellectual Disability; Networks