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Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism
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Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 34082

Special Issue Editor

Dr. M. E. Suzanne Lewis

E-Mail Website1 Website2
Guest Editor
The Department of Medical Genetics and Genomics, University of British Columbia and BC Children’s Hospital Research Institute, Vancouver, BC V6H 3N1, Canada
Interests: autism genomics; multivariant genotypes and clinical subtypes of Autism; whole exome/genome sequencing; multi-omics; precision medicine; molecular medicine and therapeutics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite its singular diagnostic label, Autism is an enormously heterogeneous spectrum, both in a clinical and an etiological sense. Autism Spectrum Disorder (ASD)—often collectively referred to as the “autisms”—is a prime candidate for ‘precision or personalized medicine’, in which understanding of cause, rather than its categorical behavioural features alone, enables the customization of healthcare, personalized interventions, and informed medical decisions tailored to the individual.

The current global understanding of ASD suffers from three major challenges. First, we have a very restricted ability to diagnose different types of ASDs: this is currently achieved entirely through symptomatic behavioural criteria rather than through any understanding of the underlying biology. As a result, our ability to target different therapies to different forms of ASD is nearly non-existent. Second, these behaviours are the endpoints of extremely complex biological systems and change over time, providing a “moving target”. Third, as with all diseases, there are underlying molecular triggers to ASDs that are exacerbated by the environment and how individuals respond to it which are not yet fully understood.

With current genomics and ‘omic’ technologies, it is now possible to capture molecular profiles of individuals with ASD through their DNA, gut and organ microbes, metabolomic byproducts, and the physical, developmental, and molecular outcomes caused by the interaction of these factors with the environment.

In this Special Issue of Genes, we welcome contributions that identify the many genomic/omic etiologies of ASD-associated phenotypes in context with their molecular underpinnings, which allow a deeper understanding of ASD beyond psychometrics alone. For example, whole exomes, genomes and gene-environment susceptible microbiomes, metabolomes, proteomes, transcriptomes, and methylomes can individually and/or collectively inform specific molecular mechanisms leading to autism. Moreover, we can begin to integrate such molecular genomic/omic data toward a deeper understanding of their effect on brain development and function, eventually identifying the key factors that cause “the autisms”, and point to the most effective, personalized, and precise treatment pathway for each unique individual on the spectrum.

Dr. M. E. Suzanne Lewis
Guest Editor

Manuscript Submission Information

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Keywords

  • autism
  • genomics
  • multi-omics
  • next-generation sequencing
  • data integration
  • precision and personalized medicine
  • molecular mechanisms and pathways
  • neurodevelopment

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Published Papers (6 papers)

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Research

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18 pages, 6675 KiB  
Article
Stratification of a Phelan–McDermid Syndrome Population Based on Their Response to Human Growth Hormone and Insulin-like Growth Factor
by Bridgette A. Moffitt, Sara M. Sarasua, Diana Ivankovic, Linda D. Ward, Kathleen Valentine, William E. Bennett, Jr., Curtis Rogers, Katy Phelan and Luigi Boccuto
Genes 2023, 14(2), 490; https://doi.org/10.3390/genes14020490 - 15 Feb 2023
Cited by 4 | Viewed by 2341
Abstract
Phelan–McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits [...] Read more.
Phelan–McDermid syndrome (PMS), caused by pathogenic variants in the SHANK3 gene or 22q13 deletions, is characterized by intellectual disability, autistic features, developmental delays, and neonatal hypotonia. Insulin-like growth factor 1 (IGF-1) and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. We assessed the metabolic profiling of 48 individuals with PMS and 50 controls and determined subpopulations by taking the top and bottom 25% of responders to hGH and IGF-1. A distinct metabolic profile for individuals with PMS showed a reduced ability to metabolize major energy sources and a higher metabolism of alternative energy sources. The analysis of the metabolic response to hGH or IGF-1 highlighted a major overlap between both high and low responders, validating the model and suggesting that the two growth factors share many target pathways. When we investigated the effect of hGH and IGF-1 on the metabolism of glucose, the correlation between the high-responder subgroups showed less similarity, whereas the low-responders were still relatively similar. Classification of individuals with PMS into subgroups based on responses to a compound can allow an investigation into pathogenic mechanisms, the identification of molecular biomarkers, an exploration of in vitro responses to candidate drugs, and eventually the selection of better candidates for clinical trials. Full article
(This article belongs to the Special Issue Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism)
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21 pages, 3730 KiB  
Article
Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome
by Manuel Munuera-Cabeza, Mónica Álvarez-Córdoba, Juan M. Suárez-Rivero, Suleva Povea-Cabello, Irene Villalón-García, Marta Talaverón-Rey, Alejandra Suárez-Carrillo, Diana Reche-López, Paula Cilleros-Holgado, Rocío Piñero-Pérez and José A. Sánchez-Alcázar
Genes 2022, 13(12), 2300; https://doi.org/10.3390/genes13122300 - 6 Dec 2022
Cited by 4 | Viewed by 4561
Abstract
Mutations in several genes involved in the epigenetic regulation of gene expression have been considered risk alterations to different intellectual disability (ID) syndromes associated with features of autism spectrum disorder (ASD). Among them are the pathogenic variants of the lysine-acetyltransferase 6A (KAT6A [...] Read more.
Mutations in several genes involved in the epigenetic regulation of gene expression have been considered risk alterations to different intellectual disability (ID) syndromes associated with features of autism spectrum disorder (ASD). Among them are the pathogenic variants of the lysine-acetyltransferase 6A (KAT6A) gene, which causes KAT6A syndrome. The KAT6A enzyme participates in a wide range of critical cellular functions, such as chromatin remodeling, gene expression, protein synthesis, cell metabolism, and replication. In this manuscript, we examined the pathophysiological alterations in fibroblasts derived from three patients harboring KAT6A mutations. We addressed survival in a stress medium, histone acetylation, protein expression patterns, and transcriptome analysis, as well as cell bioenergetics. In addition, we evaluated the therapeutic effectiveness of epigenetic modulators and mitochondrial boosting agents, such as pantothenate and L-carnitine, in correcting the mutant phenotype. Pantothenate and L-carnitine treatment increased histone acetylation and partially corrected protein and transcriptomic expression patterns in mutant KAT6A cells. Furthermore, the cell bioenergetics of mutant cells was significantly improved. Our results suggest that pantothenate and L-carnitine can significantly improve the mutant phenotype in cellular models of KAT6A syndrome. Full article
(This article belongs to the Special Issue Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism)
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10 pages, 266 KiB  
Article
Autism with Epilepsy: A Neuropsychopharmacology Update
by Roberto Canitano, Roberto Palumbi and Valeria Scandurra
Genes 2022, 13(10), 1821; https://doi.org/10.3390/genes13101821 - 8 Oct 2022
Cited by 5 | Viewed by 2994
Abstract
The association between autism spectrum disorders (ASD) and epilepsy has been extensively documented, and the estimated prevalence varies depending upon the selected population and the clinical characteristics. Currently, there are a lack of studies assessing the patient care pathways in ASD, particularly for [...] Read more.
The association between autism spectrum disorders (ASD) and epilepsy has been extensively documented, and the estimated prevalence varies depending upon the selected population and the clinical characteristics. Currently, there are a lack of studies assessing the patient care pathways in ASD, particularly for comorbidity with epilepsy, despite its personal, familial, and economic impacts. Genetic abnormalities are likely implicated in the association of ASD and epilepsy, although they are currently detectable in only a small percentage of patients, and some known genetic and medical conditions are associated with ASD and epilepsy. There is no specificity of seizure type to be expected in children and adolescents with ASD compared with other neurodevelopmental disorders or epileptic syndromes. Treatment options include antiepileptic drugs (AED) and developmentally-based early interventions for ASD. Carbamazepine and lamotrigine are the most used AED, but further studies are needed to more precisely define the most suitable medications for this specific group of children with ASD. Full article
(This article belongs to the Special Issue Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism)

Review

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14 pages, 1356 KiB  
Review
Conceptualizing Epigenetics and the Environmental Landscape of Autism Spectrum Disorders
by German Torres, Mervat Mourad, Saba Iqbal, Emmanuel Moses-Fynn, Ashani Pandita, Shriya S. Siddhartha, Riya A. Sood, Kavya Srinivasan, Riya T. Subbaiah, Alisha Tiwari and Joerg R. Leheste
Genes 2023, 14(9), 1734; https://doi.org/10.3390/genes14091734 - 30 Aug 2023
Cited by 3 | Viewed by 2965
Abstract
Complex interactions between gene variants and environmental risk factors underlie the pathophysiological pathways in major psychiatric disorders. Autism Spectrum Disorder is a neuropsychiatric condition in which susceptible alleles along with epigenetic states contribute to the mutational landscape of the ailing brain. The present [...] Read more.
Complex interactions between gene variants and environmental risk factors underlie the pathophysiological pathways in major psychiatric disorders. Autism Spectrum Disorder is a neuropsychiatric condition in which susceptible alleles along with epigenetic states contribute to the mutational landscape of the ailing brain. The present work reviews recent evolutionary, molecular, and epigenetic mechanisms potentially linked to the etiology of autism. First, we present a clinical vignette to describe clusters of maladaptive behaviors frequently diagnosed in autistic patients. Next, we microdissect brain regions pertinent to the nosology of autism, as well as cell networks from the bilateral body plan. Lastly, we catalog a number of pathogenic environments associated with disease risk factors. This set of perspectives provides emerging insights into the dynamic interplay between epigenetic and environmental variation in the development of Autism Spectrum Disorders. Full article
(This article belongs to the Special Issue Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism)
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21 pages, 758 KiB  
Review
The Autism Spectrum: Behavioral, Psychiatric and Genetic Associations
by Ann Genovese and Merlin G. Butler
Genes 2023, 14(3), 677; https://doi.org/10.3390/genes14030677 - 9 Mar 2023
Cited by 48 | Viewed by 18064
Abstract
Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of [...] Read more.
Autism spectrum disorder (ASD) consists of a group of heterogeneous genetic neurobehavioral disorders associated with developmental impairments in social communication skills and stereotypic, rigid or repetitive behaviors. We review common behavioral, psychiatric and genetic associations related to ASD. Autism affects about 2% of children with 4:1 male-to-female ratio and a heritability estimate between 70 and 90%. The etiology of ASD involves a complex interplay between inheritance and environmental factors influenced by epigenetics. Over 800 genes and dozens of genetic syndromes are associated with ASD. Novel gene–protein interactions with pathway and molecular function analyses have identified at least three functional pathways including chromatin modeling, Wnt, Notch and other signaling pathways and metabolic disturbances involving neuronal growth and dendritic spine profiles. An estimated 50% of individuals with ASD are diagnosed with chromosome deletions or duplications (e.g., 15q11.2, BP1-BP2, 16p11.2 and 15q13.3), identified syndromes (e.g., Williams, Phelan-McDermid and Shprintzen velocardiofacial) or single gene disorders. Behavioral and psychiatric conditions in autism impacted by genetics influence clinical evaluations, counseling, diagnoses, therapeutic interventions and treatment approaches. Pharmacogenetics testing is now possible to help guide the selection of psychotropic medications to treat challenging behaviors or co-occurring psychiatric conditions commonly seen in ASD. In this review of the autism spectrum disorder, behavioral, psychiatric and genetic observations and associations relevant to the evaluation and treatment of individuals with ASD are discussed. Full article
(This article belongs to the Special Issue Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism)
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Other

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11 pages, 936 KiB  
Case Report
Complex Autism Spectrum Disorder in a Patient with a Novel De Novo Heterozygous MYT1L Variant
by Silas Yip, Kristina Calli, Ying Qiao, Brett Trost, Stephen W. Scherer and M. E. Suzanne Lewis
Genes 2023, 14(12), 2122; https://doi.org/10.3390/genes14122122 - 24 Nov 2023
Cited by 1 | Viewed by 1546
Abstract
Autism spectrum disorder (ASD) comprises a group of complex neurodevelopmental features seen in many different forms due to variable causes. Highly impactful ASD-susceptibility genes are involved in pathways associated with brain development, chromatin remodeling, and transcription regulation. In this study, we investigate a [...] Read more.
Autism spectrum disorder (ASD) comprises a group of complex neurodevelopmental features seen in many different forms due to variable causes. Highly impactful ASD-susceptibility genes are involved in pathways associated with brain development, chromatin remodeling, and transcription regulation. In this study, we investigate a proband with complex ASD. Whole genome sequencing revealed a novel de novo missense mutation of a highly conserved amino acid residue (NP_001289981.1:p.His516Gln; chr2:1917275; hg38) in the MYT1L neural transcription factor gene. In combination with in silico analysis on gene effect and pathogenicity, we described the proband’s phenotype and made comparisons with previously reported cases to explore the spectrum of clinical features in MYT1L single nucleotide variant (SNV) cases. The phenotype–genotype correlation showed a high degree of clinical similarity with previously reported cases of missense variants in MYT1L, indicating MYT1L as the causal gene for the observed phenotype in our proband. The variant was also predicted to be damaging according to multiple in silico pathogenicity predicting tools. This study expands the clinical description of SNVs on the MYT1L gene and provides insight into its contribution to ASD. Full article
(This article belongs to the Special Issue Genes, Phenotypes and Molecular Mechanisms for Personalized Medicine in Autism)
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