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

Wen-Xiong Chen; Bin Liu; Lijie Zhou; Xiaoli Xiong; Jie Fu; Zhi-Fang Huang; Ting Tan; Mingxi Tang; Jun Wang; Ya-Ping Tang

doi:10.1186/s40246-022-00427-7

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

Hum Genomics. 2022 Nov 1;16(1):52. doi: 10.1186/s40246-022-00427-7.

Authors

Wen-Xiong Chen^#¹, Bin Liu^#^{2

3}, Lijie Zhou⁴, Xiaoli Xiong², Jie Fu², Zhi-Fang Huang¹, Ting Tan², Mingxi Tang⁵, Jun Wang⁴, Ya-Ping Tang^{6

7

8}

Affiliations

¹ The Assessment and Intervention Center for Autistic Children, Department of Neurology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, Guangdong, China.
² Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China.
³ Department of Biobank, Shenzhen Baoan Women's and Children's Hospital, Jinan University, Shenzhen, 518102, Guangdong, China.
⁴ Department of Pediatric Rehabilitation, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
⁵ Department of Pathology, Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China.
⁶ Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, China. yptang12@gzhmu.edu.cn.
⁷ Department of Pediatric Rehabilitation, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. yptang12@gzhmu.edu.cn.
⁸ Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China. yptang12@gzhmu.edu.cn.

^# Contributed equally.

Abstract

Background: Autism spectrum disorder (ASD) is often accompanied by intellectual disability (ID). Despite extensive studies, however, the genetic basis for this comorbidity is still not clear. In this study, we tried to develop an analyzing pipeline for de novo mutations and possible pathways related to ID phenotype in ASD. Whole-exome sequencing (WES) was performed to screen de novo mutations and candidate genes in 79 ASD children together with their parents (trios). The de novo altering genes and relative pathways which were associated with ID phenotype were analyzed. The connection nodes (genes) of above pathways were selected, and the diagnostic value of these selected genes for ID phenotype in the study population was also evaluated.

Results: 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, of these 34 genes, 22 may directly affect intelligence quotient (IQ). Further analyses revealed that these 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 all these three 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 non-verbal language (4/40).

Conclusion: We found some new genetic disposition for ASD accompanied with intellectual disability in this study. Our results may be helpful for etiologic research and early diagnoses of intellectual disability in ASD. Larger population studies and further mechanism studies are warranted.

Keywords: Autism spectrum disorder; De novo mutations; Intellectual disability; Intelligence quotient; Pathways; Whole-exome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acids / genetics
Autism Spectrum Disorder* / diagnosis
Autistic Disorder*
China
Humans
Intellectual Disability* / genetics
Language
Mutation
Proteins / metabolism

Substances

Amino Acids
Proteins