Elsevier

Clinica Chimica Acta

Volume 524, 1 January 2022, Pages 179-186
Clinica Chimica Acta

Autism spectrum disorder and comorbid neurodevelopmental disorders (ASD-NDDs): Clinical and genetic profile of a pediatric cohort

https://doi.org/10.1016/j.cca.2021.11.014Get rights and content

Highlights

  • A pediatric cohort diagnosed as ASD and comorbid NDDs.

  • Demonstrated the phenotype and genotype of ASD-NDDs with proven etiology.

  • Disclosed the underlying genetic defects and molecular pathways in ASD with NDDs.

  • Reported several genes having not been reported to be related to ASD before.

Abstract

Background

Autism spectrum disorder (ASD), a neurodevelopmental disorder, is featured by impaired social communication and restricted and repetitive behaviors and interests. ASD and comorbid neurodevelopmental disorders (ASD-NDDs), especially epilepsy and intellectual disability (ID)/global developmental delay (GDD) are frequently presented in genetic disorders. The aim of this study was to explore the clinical and genetic profile of ASD in combination with epilepsy or ID/GDD.

Methods

We retrospectively analyzed the clinical characteristics, and genetic spectrum of pediatric patients presenting ASD-NDDs with proven genetic etiology. The pathogenicity of variants was conducted by molecular geneticists and clinicians complied with the guidelines of the American College of Medical Genetics and Genomics (ACMG).

Results

Among 154 patients with ASD-NDDs, 79 (51.3%) patients gained a genetic diagnosis. Most patients (78/79, 98.7%) had comorbid ID or GDD, and 49 (49/79, 62.0%) had comorbid epilepsy. The clinical characteristics of those 79 patients were varied. 87 genetic variants were found among the 79 pedigrees. Most of the involved genes have roles in gene expression regulation (GER) and neuronal communication (NC). Most genes have been proven to be ASD-related genes, and some of them were not reported to contribute to ASD previously.

Conclusion

We summarized the genetic and clinical profile of 79 ASD-NDDs patients with proven genetic etiology. The genetic spectrum of ASD was expanded, and we highlighted a novel possible ASD candidate gene PRTG.

Introduction

Autism spectrum disorder (ASD), a group of genetically and clinically heterogeneous disorders, are characterized by social communication deficits and the presence of restricted, repetitive patterns of behavior and interests. It affects approximately 1%∼2% of children according to the Autism and Developmental Disabilities Monitoring (ADDM) Network [24]. Other neurodevelopmental disorders (NDDs), such as intellectual disability (ID) or global developmental delay (GDD), epilepsy, and attention deficit hyperactivity disorder (ADHD) can commonly appear in patients with ASD [6]. Among them, ID/GDD co-existed in 25%-42% of children with ASD [24]. Similarly, the incidence proportion of epilepsy in patients with ASD ranged from 25% to 39% [23]. And the prevalence of ASD in epileptic encephalopathy (EE) was shown to be higher than other types of epilepsy [46], especially in infantile spasm and Dravet syndrome.

The co-occurrence may result from the shared underlying mechanism of those disorders. Genetic etiology plays an essential role in ASD, ID/GDD and epilepsy, and there is genetic overlap between ASD and ID/GDD, as well as ASD and epilepsy. Some chromosomal rearrangements, copy number variants (CNVs), or single-gene disorders found in ASD are also associated with ID and epilepsy [1], [10]. Recently, in 2020, a large exome sequencing study of ASD, with 11,986 patients with ASD and 35,584 total samples, was published in Cell [40]. Researchers identified 102 ASD genes at a false discovery rate of 0.1 or less. Nearly half the implicated 102 genes (49/102, 48.0%) were more likely to lead to ASD with comorbid NDDs. They also found that most ASD risk genes played role in regulating gene expressions (i.e., chromatin remodeling, transcription regulating, and DNA/RNA binding) and neuronal communications (i.e., neurodevelopment, neurophysiology, synaptic function, cell–cell signaling, and membrane potential regulation). Those function pathways involved in ASD, like cellular signaling, transcription regulation, chromatin remodeling, and channel activity have been also found in ID and epilepsy [12], [54].

The genetic landscape of ASD is expanding. However, it’s always not easy to identify ASD risk genes with limited subjects. In the meantime, more and more genes have been confirmed to be causative genes of ID or epilepsy. Thus, we speculated that the diagnostic yield may increase when focusing on ASD patients with comorbid ID/GDD or epilepsy. Therefore, we aimed to find out the genetic diagnostic yield of ASD co-existed ID/GDD or epilepsy in our hospital at a single-center level, hoping to find new possible ASD candidate genes. More importantly, we summarized the genetic and clinical profile of those ASD patients with comorbid ID/GDD or epilepsy who had proven genetic etiology and disclose the underlying genetic defects and molecular pathways in this condition.

Section snippets

Participants

We reviewed medical records of ASD patients with other neurological comorbidities who underwent genetic evaluation like next-generation sequence (NGS) or whole-genome copy number variants (CNVs) tests in the Pediatric Department of Xiangya Hospital, Central South University. From 2015 to 2020, 154 pediatric ASD patients with comorbid ID or epilepsy who conducted genetic tests were enrolled. All participants had a clinical diagnosis of ASD by specialized child psychiatrists, based on diagnosis

Demographic features

After the process of predicting the pathogenicity of candidate variants on 154 subjects with ASD-NDDs, a total of 79 (51.3%) unrelated patients with proven genetic etiology were included in our study. 8 of 115 (7.0%, 95% CI, 2.2% − 11.7%) subjects got a molecular diagnosis from the whole-genome CNVs tests; 69 of 106 (65.1%, 95% CI, 55.9%-74.3%) from next-generation sequencing (NGS), of which 45 of 66 (68.2%, 95% CI, 56.6%-79.7%) from WES; 2 subjects from Sanger sequencing; and 1 from MLPA. The

Discussion

In our cohort, 51.3% of ASD patients achieved a genetic diagnosis and got a clinical profile of those patients. We compared the diagnostic yield to previous studies and confirmed that ASD patients with severe symptoms, specially coexisted with other NDDs, are more likely to find a genetic cause. Except for variants of common genes or CNVs related to ASD that had been published in the literature, we also identified several rare genetic variants that may contribute to ASD.

Conclusion

In conclusion, we summarized the genetic and clinical features of 79 ASD-NDDs patients with proven genetic variants. And a novel possible ASD candidate gene- PRTG was stressed in our study, which is worthy of studying in the future.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgement

We would like to thank the patients and their parents for their participation in this study.

Funding

This work was supported by grants from the National Natural Science Foundation of China (NO.81771408), the Hunan Key Research and Development Program (NO.2019SK2081), and the National Key Research and Development Program of China (NO.2016YFC1306202).

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