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Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 297-301

Influence of De novo mutation in autism

1 Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
2 Department of Human Genetics and Molecular Biology, Medical Genetics and Epigenetics Laboratory, Bharathiar University, Coimbatore, Tamil Nadu, India

Date of Submission26-Apr-2020
Date of Acceptance02-May-2020
Date of Web Publication30-Dec-2020

Correspondence Address:
Dr. Vijaya Anand Arumugam
Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore - 641 046, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_63_20

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Autism and autism spectrum disorders (ASD) affects the areas of social awareness and interaction, verbal and nonverbal communication, and behaviors and interests, which are grouped among neurobehavioral disorders. One in 68 children is affected with ASD according to the estimate from the Center for Disease Control and Prevention's autism and developmental disabilities monitoring network and an increasing prevalence observed worldwide. A characteristic heterogeneity in ASD determined genetic variability as a major contributor. Whole-exome sequencing of ASD individuals revealed that discrete de novo mutation (single-nucleotide variation or small indels) also contribute to the overall genetic risk of ASD apart from rare genetic variation affecting single nucleotides of protein-coding DNA or rare genomic copy number variants as assessed through other high-throughput genomic methods. These genes are involved in synaptic transmission and regulated during brain development by acting upstream or downstream of Wingless- related integration site (WNT), bone morphogenetic proteins/transforming growth factor-β, sonic hedgehog, fibroblast growth factor, and retinoic acid signaling pathways. The current review focuses on genes involved in synaptic function, undergoing de novo mutation leading to ASD condition.

Keywords: Autism, de novo mutation, synaptic transmission and whole-exome sequencing

How to cite this article:
Sanjeev AM, Kathirvel B, Mohandass K, Arumugam VA. Influence of De novo mutation in autism. Biomed Biotechnol Res J 2020;4:297-301

How to cite this URL:
Sanjeev AM, Kathirvel B, Mohandass K, Arumugam VA. Influence of De novo mutation in autism. Biomed Biotechnol Res J [serial online] 2020 [cited 2023 May 30];4:297-301. Available from: https://www.bmbtrj.org/text.asp?2020/4/4/297/305647

  Introduction Top

Autism and autism spectrum disorders (ASD) are a group of neurobehavioral disorders that manifest as a deficit with varying severity in one or more of three key areas: social awareness and interactions, verbal and nonverbal communication, and restricted (stereotypical) behaviors and interests (OMIM 209850). Autism as a disorder was first identified by Leo Kanner and Hans Asperger based on the observation on very small cohorts of children.[1]

  Prevalence and Incidence Top

According to the estimates from the Centre for Disease Control and Prevention Autism and Developmental Disabilities Monitoring Network, approximately 1 in 68 children are being identified with ASD.[2] These heterogeneous neurodevelopmental disorders are estimated to affect 1 in 68 (or 147 in 10,000 reported in 2010 for the birth year 2002) in the United States, which is compared to the previous (2008) estimate of 1 in 88 is 30% higher. The high rates of autistic disorder reported in other countries include Sweden with 72.6 cases/10,000 in 1999 and South Korea with 94 cases/10,000 in 2011.[3]

Further, the prevalence of ASD in nine countries in Asia (East Asia: Korea; West Asia: Lebanon, Bangladesh, Iran, Israeli; and South Asia: India, China, Nepal, Sri Lanka) was estimated by meta-analysis. It was found that the estimate of ASD prevalence in Asia was 0.36%, ranging from 0.06% in Iran to 2.64% in Korea. It was also found that prevalence in East Asia (0.51%) was higher compared to West Asia (0.35%) and South Asia (0.31%).[4]

The ASD prevalence studies in India were conducted by meta-analysis, in which two studies where from South India (Kerala), one from Eastern India (Kolkata), and one from North India (Himachal Pradesh) and the analysis was performed in the rural and urban settings. The study showed a pooled percentage prevalence of 0.11 within children aged 1–18 years in rural settings; and a pooled percentage prevalence of 0.09 within children aged 0–15 years in an urban setting. In both rural and urban community-based settings in India, there is a low percentage prevalence of ASD.[5]

The single-stage cross-sectional community survey for toddlers aged between 13 and 24 months was conducted in the State of Kerala, South India. In this study, toddlers at risk for ASD were identified to be 5.5% using the modified checklist for Autism in toddlers-revised (M CHAT-R) total and 2.7% using the “Best-Seven” of M-CHAT-R. Of the 341 toddlers (5.5%), who had a total score of 3 or above on the M-CHAT-R, 259 toddlers (4.2%) scored between 3 and 7 and were considered to have a medium risk, and 82 toddlers (1.3%) scored between 8 and 20 and were considered to be at high-risk ASD and toddlers at risk as per “Best Seven” were 162 (2.7%).[6]

  Clinical Features and Diagnosis of Autism Top

In 2013, the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) changed ASD diagnostic criteria, eliminating diagnostic subtypes (which had included autistic disorder, Asperger's syndrome, and Pervasive Developmental Disabilities) and creating a single category formally designated as ASD. The DSM-5 has combined previously distinct social and communication deficit criteria into one domain and has also added a new diagnosis, social communication disorder, and outside of ASD. Based on the above criteria, the clinical features and diagnosis of ASD tabulated in [Table 1].[7]
Table 1: Clinical features and diagnosis criteria for autism spectrum disorder

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  Screening for Autism Top

These disorders are expressed early in life with an age of onset around 18 months.[8] Standardized diagnostic instruments are available for ASD, including the screening tool for autism in toddlers and young children (STAT; a 20-min observation for young children) and Autism Diagnostic Observation Schedule (a 45-min observation done by a skilled professional, available in different formats for people of different language levels and ages, from 12 months to adulthood). For more comprehensive developmental history, caregiver interviews, such as the Autism Diagnostic Interview-Revised or the computer-generated developmental, dimensional, and diagnostic interview are used. A variety of scales, such as the Childhood Autism Rating Scale, Social Responsiveness Scale, and the Social Communication Questionnaire are used to assess children's symptoms.[9]

  Treatment and Management of Autism Top

There is no cure for ASD, but there are number of drugs available for atypical antipsychotics like “risperidone” and “aripiprazole” may help to reduce aggression, irritability, and self-injurious behavior in children older than 5 years.[10]

Thus, treatment for ASD is mainly intended to reduce the abnormal behavioral symptoms. The treatment strategies, along with antipsychotics and anti-anxiety drugs, include behavioral therapy, special educational approaches, speech therapy, and cognitive therapy, which can improve the symptoms associated with ASD and incorporation of an adequate diet plan aids to overcome several comorbidities associated with ASD. Dietary elimination of casein and gluten showed an improved disease status than normal diet consuming ASD individuals. While dietary supplementation of deficit nutrients such as omega-3 fatty acids, probiotics, vitamins, folic acid, and several other minerals helped to reduce some autism symptoms. In addition, there is a necessity for sufficient intake of nutrients, including Vitamin B12, folate, and food-containing Docosahexaenoic acid (DHA), to further reduce or reverse any adverse effects of nutrient deficiency.[11]

The management of ASD is done to build cognitive, communication, and social skills, promote learning and problem solving, reduce maladaptive behavior, treat comorbid conditions, counsel parents, consider educational placement, prepare individuals and families for adolescence and adulthood, and provide coping assistance to families.[10]

  De novo Mutation in Autism Top

Heterogeneity in etiology, phenotype, and outcome are trademarks of ASD. The marked heterogeneity of ASDs has led to ideas giving consideration to multiple etiologies and distinct clinical entities.[12] The heterogeneity of clinical entities is, in part, a function of the multiple genes involved, the numerous of environmental factors impacting the developmental course of symptom expression, and the co-occurrence of medical and mental health dysfunctions in ASD. The three factors contributing to the heterogeneity of ASD include genetic variability, co-morbidity, and gender.[13]

Genetic variability is considered to be a major contributor to the heterogeneity of ASD. There is an increasing pool of ASD genes due to high-throughput genomic methods, which in turn expand the genetic variability associated with heterogeneity.[14] The significant ASD risk factors accepted now include rare genetic variation affecting single nucleotides of protein-coding DNA as well as rare genomic copy number variants. Whole-exome sequencing on ASD families have been conducted by several groups, and these studies, in turn, indicate that discrete de novo mutation (single nucleotide variation or small indels) contribute to the overall genetic risk of ASD?.[15]

Trio genetic association studies (parents and affected pro-band) to study de novo mutation and to find mutations in the pro-band that were not present in either parent have been used. Accordingly, whole-exome sequencing to reveal the genetic architecture of ASD has also been employed. These studies showed there is the loss of function mutations, including missense de novo mutations and nonsense de novo mutations, which in turn include different subtypes: frameshift, splice site, and stop gain. Such missense variants may produce a gain in function, and genes carrying two or more such mutations were seen to be more likely to be pathogenic in ASD.[16]

Venkataraman et al. 2017[17] reported that the genes involved in synaptic elimination are significantly enriched for autism de novo mutations, pointing to deregulation in synaptic elimination as a potential pathogenic mechanism for ASD and synaptic elimination, a part of the larger synaptic homeostatic mechanism, contributes to higher structural and functional connectivity underlying cognitive functions through the removal of synaptic structures. The study has also reported that there is a possibility that ASD associated gene products can be involved in neurite development, which is one of the important criteria of the central nervous system development and function.[17]

There was two-fold enrichment in autism compared to a control group when whole-exome sequencing study was done based on inherited homozygous or compound heterozygous loss-of-function mutations. It considered that YWHAZ and dystrophin-related protein 2 gene (DRP2) as strong novel ASD candidate genes. The YWHAZ gene, encodes a postsynaptic protein, and this protein interacts physically with numerous ASD gene products such as TSC1, TSC2, DISC1, UBE3A and CYFIP1 and these proteins are also involved in various processes including cell cycle, transcription, neuronal development, migration, and neurite outgrowth and are expressed highly in the brain. The X-linked DRP2 is another good ASD candidate expressed mainly in the brain and spinal cord, and this gene regulates the myelination of Schwann cells by forming a complex with periaxin and dystroglycan.[18]

Whole-exome sequencing study of 30 individuals with sporadic ASD and their parents, identified 37 genes with 38 de novo single-nucleotide variations and 33 single nucleotide variant (3 nonsense, 27 nonsynonymous and 3 possible splice site) and 32 genes were considered for the further analysis. Among these POGZ, PLEKHA4, PCNX, PRKD2, and HERC1 are reported to be genes with de novo SNVs in ASD, HERC1 regulates Purkinje cell physiology in the cerebellum and POGZ along with PRKD2 regulate neural functions, such as neurite development. Several ASD-associated gene products such as EPAC2, TAOK2, and PTEN identified are involved in the maintenance of axonal and dendritic growth.[19]

A conclusive genetic diagnosis was obtained in seven of 80 children identified by whole-exome sequencing, in which an overall diagnostic yield was 8.8% (9.2% in the group of ASD and 6.7% in the group of suspected ASD) and a total of seven variants each identified in a different gene was detected and validated. In total, seven genes (CHD8, AFF2, ADNP, POGZ, SHANK3, IL1RAPL1, and PTEN) with estimated pathogenic variations were also identified. SHANK3 was a gene coding a scaffolding protein that is rich in postsynaptic densities of excitatory synapses. Two variants (one missense and one de novo loss of function) were identified in two X-chromosome genes (AFF2 and IL1RAPL). AFF2, whose function is to code a putative transcriptional activator, is in turn turn, a member of the AF4/FMR2 gene family, earlier associated with ASD and mental retardation, X-linked. ASD individual with a de novo loss of function variation in IL1RAPL1, in which this gene is highly expressed in postnatal brain structures and functions in the hippocampal memory system, suggest a key role in the physiological processes underlying memory and learning abilities.[20]

In other studies, BRSK2 meets genome-wide significance as a new ASD risk gene, and additional members with ASD having de novo damaging variants include PAX5, NR4A2, RALGAPB, and DPP6 genes, which are expressed with regard to cortical layer specificity in the human developing brain. Few genes (BRSK2, ITSN1, FEZF2, RALGAPB, NR4A2, EGR3, DPP6, CPZ, SH3RF3, and CLCN4) are expressed in developing fetal human cortex. ITSN1 and DPP6 are part of the postsynaptic density components in the human neocortex. In central nervous system development, FEZF2 and PAX5 are involved in transcription regulation. KDM1B is a known chromatin modifier, and EGR3 has been implicated in neurodevelopment.[21]

De novo small indels and point substitutions were revealed on exome sequencing 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, which mostly comes from the paternal line. There are no significantly higher numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frameshifts) are double in frequency. Many of the disrupted genes studied are connected to the fragile X protein, fragile X mental retardation gene product (FMRP), enforcing links between autism and synaptic plasticity. There are overlaps with the most likely candidate genes from CNV study: NRXN1 and PHF2, the first one is considered to be casual for ASD, and the last one corresponds to mRNAs whose translation may be controlled by the FMRP.[22]

Guo et al., 2018[23] reported RALGAPB gene is also a promising risk gene for follow-up as recurrent? Likely-Gene Disrupting (LGD) de novo mutations were identified in ASD. RALGAPB encodes a Ras-like GTPase-activating protein. Several genes encoding the GTPase-activating protein have been associated with autism risks, such as SYNGAP1, TSC2, ARHGAP, and ARHGAP.[23]

Several mutations were identified in neurexin1 and neuroligin1, and they are components of neurexin-neuroligin synaptic cell adhesion complex. According to exome studies, many of the top genes are novel candidates for ASD, including the strongest overall association CHD8, an ATP-dependent chromo-domain helicase that directly regulates CTNNB1 as well as p53 pathway. The next with truncating mutation in ASD cases is SCN2A, and this gene encodes voltage-gated sodium channel expressed in the brain, and it is the reason for generation and propagation of action potential in neurons. Another is DYRK1A, for which truncating mutations were discovered in autism pro-bands, and this gene is a key regulator of brain growth, affecting vast aspects of neurogenesis, including neuronal proliferation, morphogenesis, differentiation, and maturation. Truncating mutations, also with each of GRIN2B, SYN-GAP1, and TBR1 shows the importance of excitatory/glutamatergic signaling in ASD. GRIN2B forms a subunit of NMD receptors associated with learning and memory and also in targeted sequencing linked to neurodevelopmental disorders as discovered in ASD.[24]

Whole exome sequencing of ASD has identified multiple de novo indels, in which there is the loss of the epigenetic regulator gene, Lysine (K)-specific methyltransferase 2E and RIMS1 gene, which regulates synaptic vesicle release. Similarly, de novo missense mutations in the gene lead to loss of function of GLRA2 plays a known role in axonal branching, synaptic plasticity, cognition, and memory, which are deregulated when the gene is mutated. A study identified de novo copy number variation in genes involved in several pathways such as neuroactive ligand-receptor interaction pathways, calcium signaling pathways, and metabolic pathways such as BDKRB1, BDKRB2, AP2M1, SPTA1, PTH1R, CYP2E1, PLCD3, F2RL1, UQCRC2, LILRB3, RPS9, and COL11A2.[11]

  Biological Pathways Associated with Autism Spectrum Disorder Top

In vertebrates and invertebrates, ASD causal genes can act upstream or downstream of WNT [Figure 1],[25] sonic hedgehog [Figure 2],[25] bone morphogenetic proteins/transforming growth factor-β [Figure 3],[25] fibroblast growth factor, and retinoic acid [Figure 4][25] signaling pathways. ASD and other neurodevelopmental disorders seem to be caused by the alteration in these signaling pathways during brain development.
Figure 1: Possible interactions between autism spectrum disorders causal genes and WNT signaling

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Figure 2: Possible interactions between autism spectrum disorders causal genes and sonic hedgehog signaling

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Figure 3: Autism spectrum disorders causal genes affecting bone morphogenetic proteins signaling and potential interaction with other signaling pathways

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Figure 4: Possible interactions between autism spectrum disorders causal genes and retinoic acid signaling

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  Conclusion Top

The prevalence of ASD is increasing, and multiple genes are involved in causing autism. Whole-exome sequencing done on ASD individuals showed that de novo mutation was also one of the genetic causes for ASD. These genes are mainly involved in signal transmission functioning and are present in the brain. They undergo de novo mutation, including a single-nucleotide variant affecting various signaling pathways.


The authors would like to thank the authorities of the University for rendering the support in completing the manuscript

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Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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