Autism spectrum disorders (ASD) are a collection of neurodevelopmental disorders that are currently diagnosed solely on the basis of abnormal reciprocal language and social development as well as stereotyped behaviors. Without genetic or molecular markers for screening, individuals with ASD are typically not diagnosed before the age of 2, with milder cases diagnosed much later. Because early diagnosis is tantamount to early behavioral intervention which has been shown to improve individual outcomes, an objective biomarker test that can diagnose at-risk children perinatally is a medical imperative. The rapidly increasing prevalence of ASD in the United States (now estimated at 1 in 88 individuals) also makes early diagnosis and intervention a public health imperative. This article reviews recent genome-wide (genomic) approaches to the identification of disease markers that may be used not only for diagnosis of ASD, but also for the informed development of novel drugs that target specific core symptoms of ASD. Because of the heterogeneity of clinical manifestations associated with the ASD population, this review also addresses the importance of dividing individuals with ASD into clinically relevant subphenotypes in the quest to identify appropriate biomarkers.

Valerie W. Hu

Subphenotype-Dependent Disease Markers for Diagnosis and Personalized Treatment of Autism Spectrum Disorders

Autism spectrum disorders (ASD) is a neurodevelopmental disease with complex genetics; however, the genes that are responsible for this disease still remain mostly unknown. Here, we focus on the FOXP family of transcription factors as there is emerging evidence strongly linking these genes to ASD and other genes implicated in ASD. The FOXP family of genes includes three genes expressed in the central nervous system: FOXP1, FOPX2, and FOXP4. This unique group of transcription factors has known functions in brain development as well as the evolution of language. We will also discuss the other genes including transcriptional targets of FOXP genes that have been found to be associated with language and may be important in the pathophysiology of ASD. Finally, we will review the emerging animal models currently being used to study the function of the FOXP genes within the context of ASD symptomology. The combination of gene expression and animal behavior is critical for elucidating how genes such as the FOXP family members are key players within the framework of the developing brain.

J. Michael Bowers

Genevieve Konopka

The Role of the FOXP Family of Transcription Factors in ASD

The neural and genetic bases of human language development and associated neurodevelopmental disorders, including autism spectrum disorder (ASD), in which language impairment represents a core deficit, are poorly understood. Given that no single animal model can fully capture the behavioral and genetic complexity of ASD, work in songbird, an experimentally tractable animal model of vocal learning, can complement the valuable tool of rodent genetic models and contribute important insights to our understanding of the communication deficits observed in ASD. Like humans, but unlike traditional laboratory animals such as rodents or non-human primates, songbirds exhibit the capacity of vocal learning, a key subcomponent of language. Human speech and birdsong reveal important parallels, highlighting similar developmental critical periods, a homologous cortico-basal ganglia-thalamic circuitry, and a critical role for social influences in the learning of vocalizations. Here I highlight recent advances in using the songbird model to probe the cellular and molecular mechanisms underlying the formation and function of neural circuitry for birdsong and, by analogy, human language, with the ultimate goal of identifying any shared or human unique biological pathways underscoring language development and its disruption in ASD.

S. Carmen Panaitof

A Songbird Animal Model for Dissecting the Genetic Bases of Autism Spectrum Disorder

Irina Voineagu

Autism: From Genetics to Biomarkers

Mutations in the MECP2 gene are found in a large proportion of girls with Rett Syndrome. Despite extensive research, the principal role of MeCP2 protein remains elusive. Is MeCP2 a regulator of genes, acting in concert with co-activators and co-repressors, predominantly as an activator of target genes or is it a methyl CpG binding protein acting globally to change the chromatin state and to supress transcription from repeat elements? If MeCP2 has no specific targets in the genome, what causes the differential expression of specific genes in the Mecp2 knockout mouse brain? We discuss the discrepancies in current data and propose a hypothesis to reconcile some differences in the two viewpoints. Since transcripts from repeat elements contribute to piRNA biogenesis, we propose that piRNA levels may be higher in the absence of MeCP2 and that increased piRNA levels may contribute to the mis-regulation of some genes seen in the Mecp2 knockout mouse brain. We provide preliminary data showing an increase in piRNAs in the Mecp2 knockout mouse cerebellum. Our investigation suggests that global piRNA levels may be elevated in the Mecp2 knockout mouse cerebellum and strongly supports further investigation of piRNAs in Rett syndrome.

Alka Saxena

Dave Tang

Piero Carninci

piRNAs Warrant Investigation in Rett Syndrome: An Omics Perspective

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental diseases characterized by a triad of specific behavioral traits: abnormal social interactions, communication deficits and stereotyped or repetitive behaviors. Several recent studies showed that ASDs have a strong genetic basis, contributing to the discovery of a number of ASD-associated genes. Due to the genetic complexity of these disorders, mouse strains with targeted deletion of ASD genes have become an essential tool to investigate the molecular and neurodevelopmental mechanisms underlying ASD. Here we will review the most relevant genetic mouse models developed by targeted inactivation of ASD-associated genes, and discuss their importance for the development of novel pharmacological therapies of these disorders.

Giovanni Provenzano

Giulia Zunino

Sacha Genovesi

Paola Sgad&#xf3;

Yuri Bozzi

Mutant Mouse Models of Autism Spectrum Disorders

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Disease Markers publishes papers related to the identification of disease markers, the elucidation of their role and mechanism, as well as their application in the prognosis, diagnosis and treatment of diseases.

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Chief Editor Paola Gazzaniga is an Associate Professor in the Department of Molecular Medicine at Sapienza University of Rome, Italy. Her core research focuses on liquid biopsies in patients with solid tumors.

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Disease Markers

This Issue is now open for submissions.
Papers are published upon acceptance, regardless of the Special Issue publication date.

Disease Markers

Autism: From Genetics to Biomarkers

Autism: From Genetics to Biomarkers

Articles

Subphenotype-Dependent Disease Markers for Diagnosis and Personalized Treatment of Autism Spectrum Disorders

The Role of the FOXP Family of Transcription Factors in ASD

A Songbird Animal Model for Dissecting the Genetic Bases of Autism Spectrum Disorder

Autism: From Genetics to Biomarkers

piRNAs Warrant Investigation in Rett Syndrome: An Omics Perspective

Mutant Mouse Models of Autism Spectrum Disorders