1.Introduction

Autism Spectrum Disorder (ASD) is designated as a developmental condition, with supporting evidence derived from studies showing a high concordance rate among monozygotic twins, ranging between 73% and 95%. Furthermore, twin studies have highlighted a remarkable heritability of over 90% for ASD. Additionally, there is a notable risk of recurrence within sibling pairs, with approximately 5-6% of siblings manifesting the complete disorder and a broader spectrum of ASD affecting around 15-25% of them [1]. The core characteristics of Autism Spectrum Disorder (ASD) encompass deficiencies in social interaction and verbal communication, coupled with repetitive and rigid behaviours.

2.Background

Autism exhibits a polygenic inheritance pattern. Genetic anomalies, including abnormal chromosomes or candidate genes associated with autism, give rise to abnormal expression of proteins, glycoproteins, enzymes, receptors, and neurotransmitters crucial for neurological development. Consequently, this abnormal expression disrupts the typical development of both the cerebrum and cerebellum, establishing a biological foundation for autism. In combination with additional factors, these disruptions ultimately culminate in specific neurodevelopmental disorders, manifesting as the characteristic symptoms of autism.

3.Methodology

To reassess the autism candidate genes and provide a robust review of the published evidence, we systematically searched China Knowledge, Web of Science, etc., and used the following strategy to search the databases: (ALL=(ASD)) OR ALL=(autism)) OR ALL=(autism genetics)) OR ALL=(autism risk gene)) OR ALL=(pervasive developmental disorder)) OR ALL = (autism risk gene)) OR ALL=(autism candidate gene)) OR ALL=(autism genetic variation)) OR ALL=(autism shank3)) OR ALL=(autism RELN). A total of 72 articles were identified through the initial search. After duplicates were removed, 65 articles were screened for eligibility. Of the remaining 48 articles that were fully reviewed, 21 eligible articles were selected for data extraction (Figure 1).

Figure 1. Flow chart of literature identification and selection

4.Finding

We extracted the information by searching China Knowledge, Web of Science, etc., and summarized the risk genes related to autism, such as SHANK3, TRIM33, RELN, CHD8, NRXN1, and ZNF804A, intending to evaluate the candidate genes of autism once again and provide a powerful overview of the published evidence(Table1). Investigations into potential ASD genes have leveraged next-generation sequencing (NGS) and animal models as key strategies. NGS has facilitated the discovery of disruptive genetic variations across the protein-coding segments of the genome. In conjunction with extensive cohorts and advanced statistical techniques, these NGS approaches have transformed the landscape of ASD gene identification. Additionally, NGS has played a pivotal role in generating functional genetic information, including gene expression profiles, which aids in elucidating the neurobiological ramifications of disrupting ASD-linked genes [2]. Mice with SHANK3 mutations, specifically those lacking the SHANK3 gene, have offered fresh perspectives on the brain's higher functions specifically linked to SHANK3, as well as on developmental and psychiatric disorders associated with SHANK3 alterations.

Zhang et al. found that the genetic variant rs10497655 exhibited a statistically significant association with autism spectrum disorder (ASD) (P=0.007851), exerting a notable influence on ZNF804A expression [3]. Specifically, individuals homozygous for the T-risk allele demonstrated decreased levels of ZNF804A expression in human fetal brains. This finding was observed in a cohort comprising a total of 427 trio families. Li et al. identified a statistically significant genetic correlation between autism and four SNPs within the DAB1 gene: rs12035887 (G allele, p = 0.0006), rs3738556 (G allele, p = 0.0044), rs1202773 (A allele, p = 0.0048), and rs12740765 (T allele, p = 0.0196) [4]. These results imply that variations in DAB1 may be associated with autism and potentially elevate the risk for the condition. Cuchillo-Ibáñez et al. showed that children diagnosed with autism exhibited higher concentrations of Reelin (0.44 ± 0.03 ng/ml, n = 40) in comparison to those without autism spectrum disorder (ASD), who had lower levels (0.32 ± 0.03 ng/ml, n = 19) [5]. This difference was statistically significant (p < 0.01).

Table 1. Information on risk genes is included in the review.

5.Discussion

In recent years, advancements in high-throughput genomic technologies have enabled scientists to uncover numerous genes that pose risks for autism spectrum disorder. These genes may encompass common variations like single nucleotide polymorphisms (SNPs) or rare genetic anomalies. This discussion focuses on the identified risk genes.

SHANK3: Among the structural chromosomal variations frequently observed in autism spectrum disorder, 22q stands out as a prominent one. The condition arising from the terminal deletion of the 22q segment is known as 22q13.3 deletion syndrome. SHANK3 is a compelling candidate gene implicated in the causation of 22q13.3 deletion syndrome [15]. Durand et al. showed that in ASD families, people with absent language and mental retardation carried the deletion of 22q13 [16]. The breakpoint of the deletion was identified within intron 8 of the SHANK3 gene. Furthermore, patients diagnosed with bipolar disorders were found to have duplications of the SHANK3 gene. Mice overexpressing Shank3 exhibited synaptic abnormalities and displayed manic-like behavioural phenotypes [17].

CHD8: Genetic alterations in the gene that encodes the chromodomain helicase DNA-binding protein 8 (CHD8) represent a potent risk factor for autism spectrum disorder (ASD). Heterozygous mutant mice lacking one functional copy of the Chd8 gene exhibit macrocephaly heightened anxiety-related behaviours, perturbations in social interactions, and cognitive impairments [18]. In Chd8+/− mice, there are observable changes. Specifically, brain growth is modified, and the expression of crucial neurodevelopmental genes, which are responsible for governing long-distance brain connections, is reduced. Subsequently, unique abnormalities surface in the functional connectivity of the brain. Suetterlin et al. reported that heterozygous Chd8 mutant mice exhibited an enlargement of brain size, delayed motor development, increased interocular distance (hypertelorism), marked hypoactivity, and aberrant responses to social cues [19].

RELN: Reelin, a secreted extracellular matrix protein, is pivotal in neuronal migration and cortical lamination during embryonic brain development. Encoded by the RELN gene situated on chromosome 7q22, its expression is tightly regulated by intricate epigenetic mechanisms. Mutations within the RELN gene have been implicated in the pathogenesis of autism spectrum disorders [20]. Reelin has been identified as a potential gene associated with autism. Researchers have noted a correlation between an increased number of CGG repeats within the 5' untranslated region (5'UTR) of the RELN gene and decreased expression of Reelin. Importantly, these genetic variants are more frequently observed in individuals diagnosed with autism [21].

6.Conclusion

In conclusion, ten candidate genes were identified from the extracted data. Autism spectrum disorder (ASD) encompasses a multifaceted aetiology and biochemical anomalies that remain incompletely understood. The intricate causes and biochemical disturbances of ASD necessitate further elucidation, highlighting the paramount importance of ASD prevention. Investigating autism risk genes will furnish clinicians and healthcare policymakers with pertinent evidence-based data to advance the prevention and management of ASD.

7.Challenge

Certain genetic sequence variations remain unknown in the pathogenesis of autism, and numerous studies have yielded preliminary findings due to constraints such as limited sample sizes and incomplete functional annotation of missense variants. Validation of these results necessitates larger sample sizes and independent replication studies. Given that the investigation of autism risk genes will furnish crucial evidence-based insights for clinicians and healthcare policymakers, future research on autism spectrum disorder (ASD) holds particular significance.