Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability

Carlo Sala, Chiara Verpelli, Carlo Sala, Chiara Verpelli

• Publisher: Academic Press
• Year: 2016
• ISBN:
  9780128005330
• Topic: Ciencias biológicas
• Subtopic: Neurociencia

Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability provides the latest information on Autism spectrum disorders (ASDs), the lifelong neurodevelopmental disorders that present in early childhood and affect how individuals communicate and relate to others and their surroundings.

In addition, three quarters of ASD patients also manifest severe intellectual disability. Though certain genes have been implicated, ASDs remain largely a mystery, and research looking into causes and cellular deficits are crucial for better understanding of neurodevelopmental disorders.

Despite the prevalence and insidious nature of this disorder, this book remains to be an extensive resource of information and background on the state of current research in the field.

The book serves as a reference for this purpose, and discusses the crucial role synaptic activity plays in proper brain function. In addition, the volume discusses the neurodevelopmental synaptopathies and serves as a resource for scientists and clinicians in all biomedical science specialties. This research has been crucial for recent studies that have provided a rationale for the development of pharmacological agents able to counteract functional synaptic anomalies and potentially ameliorate some ASD symptoms.

• Introduces the genetic and non-genetic causes of autism and associated intellectual disabilities
• Describes the genes implicated in autistic spectrum disorders and their function
• Considers major individual genetic causes of autism, Rett syndrome, Fragile X syndrome, and other autism spectrum disorders, as well as their classification as synaptopathies
• Presents a thorough discussion of the clinical aspects of multiple neurodevelopmental disorders and the experimental models that exist to study their pathophysiology in vitro and in vivo, including animal models and patient-derived stem cell culture

Part I

Autism Spectrum Disorders and Intellectual Disability:Genetic and Non-Genetic Causes

Outline

Chapter 1. Experimental Tools for the Identification of Specific Genes in Autism Spectrum Disorders and Intellectual Disability

Chapter 2. Genetic Causes of Autism Spectrum Disorders

Chapter 3. Genetics of X-Linked Intellectual Disability

Chapter 4. Genetic Causes of Intellectual Disability: The Genes Controlling Cortical Development

Chapter 5. Immune Dysfunction in Autism Spectrum Disorder

Chapter 1

Experimental Tools for the Identification of Specific Genes in Autism Spectrum Disorders and Intellectual Disability

Yiping Shen^1,2,3,4, and Xiaohong Gong^{5,6 1}Department of Pathology, Harvard Medical School, Boston, MA, USA ²Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA, USA ³Guangxi Maternal and Child Health Hospital, Nanning, GuangXi, China ⁴Shanghai Jiao Tong University School of Medicine, Shanghai, China ⁵School of Life Sciences, Fudan University, Shanghai, China ⁶Institute of Science and Technology for Brain-Like Intelligence, Fudan University, Shanghai, China

Abstract

Technological advancements for interrogating genomic variants continue to facilitate discoveries of the genetic causes of intellectual disability (ID) and autism spectrum disorders (ASD), both of which are neurodevelopmental disorders known to have a strong genetic basis. In this chapter we discuss the major methods and approaches that have had significant roles in revealing genes and genomic regions associated with ID and ASD. Linkage analysis followed by candidate gene sequencing and positional cloning in patients with genomic rearrangements have been largely responsible for the success of identifying X-linked and autosomal dominant ID/ASD genes. Autozygosity mapping has a unique role in identifying recessive ID/ASD genes. Exome and whole-genome sequencing has provided unprecedented power for genotyping, and the data have provided us with a broader understanding of the association of de novo variants with ID and ASD. We believe that a better understanding of the genetic underpinnings will lead to better diagnosis, management, and treatment for patients with ID and ASD.

Keywords

Autozygosity mapping; Balanced translocation breakpoint mapping; Candidate gene approach; Copy number variations; Exome sequencing; Linkage analysis; Next-generation sequencing; Positional mapping; Whole-genome sequencing

Outline

Positional Mapping 3

Linkage Mapping 3

Balanced Translocation Breakpoint Mapping 4

Autozygosity Mapping 4

Candidate Gene Approach 6

Copy Number Variations 7

Genome-wide CNV Detection Methods 7

Targeted CNV Detection Methods 8

Next-Generation Sequencing 8

Next-Generation Sequencing Platforms 9

Whole-Genome Sequencing Studies in ID and ASD 10

Exome Sequencing in ID and ASD 10

Conclusion 11

References 11

Positional Mapping

Linkage Mapping

Genetic linkage is the tendency of genes that are located proximally to each other on a chromosome to be inherited together during meiosis. For most neuropsychiatric diseases whose underlying pathomechanisms are largely unknown, linkage analysis is a powerful tool to detect the chromosomal location of disease genes. Genome-wide linkage studies generally use 300–500 microsatellites evenly spanning the entire genome, with an average resolution of 5–10 centimorgans (cM) (1 cM ≈ 1 million base pairs [Mbp]). A centimorgan is defined as the distance between chromosome positions for which the expected average number of intervening chromosomal crossovers in a single generation is 0.01. Microsatellites, or short tandem repeats, are repeat sequences of two to five base pairs (bp). Microsatellites are good markers for linkage studies because they have high heterozygosity. Although single nucleotide polymorphisms (SNPs) are biallelic and not as highly polymorphic as microsatellites, they are the most common type of genomic variation (about 1 SNP in 1000 bp) and have better coverage for small chromosomal regions.

Linkage analysis could be either parametric or nonparametric. Parametric linkage analysis is the most powerful statistical method to test for linkage. It requires prior knowledge of the inheritance model, the allele frequency, and the penetrance. The test statistic is called the logarithm of odds (LOD) score. An LOD score higher than 3.0 is generally accepted as the evidence supporting linkage, whereas an LOD score lower than −2.0 is considered evidence against linkage. Nonparametric linkage analysis is a model-free approach that studies the probability of an allele being identical by descent (IBD) in pairs of relatives with same phenotype. Many computer programs for linkage analysis are available: for example, LIPED, LINKAGE, FastLINK, MENDEL, GENEHUNTER, MapMaker and CRI-MAP for parametric linkage analysis, and ANALYZER for nonparametric linkage analysis.

The X chromosome spans about 155 Mbp and contains 800–900 genes out of 20,000–25,000 total genes in the human genome. X-linked intellectual disability (XLID) is a common cause of monogenic intellectual disability (ID), accounting for 8–12% of all ID cases in males.^1–4 X-linked gene defects usually lead to severe clinic symptoms in males because they have only one X chromosome, whereas female carriers may have no or milder symptoms. The hemizygosity of males in X chromosome makes the linkage mapping strategy especially successful in the identification of X-linked genes. In the review of Lubs et al. in 2012, 102 XLID genes were associated with 81 XLID syndromes and with 35 families with nonsyndromal XLID.⁵

Linkage analysis is a useful tool as the first step to map the disease gene to a refined region; the actual causal gene is then usually identified after sequencing analysis of appropriate candidate genes within this region. For example, in a three-generation Norwegian family with XLID, a panel of 48 polymorphic microsatellite markers with an average distance of 3.9 cM on the X chromosome was genotyped in three affected males and seven unaffected relatives.⁶ Multipoint parametric linkage analysis achieved a maximum LOD score of 1.50 at the Xq24-q27.3 interval. Candidate gene sequencing identified a deletion in the SLC9A6 gene, which is located to Xq26. The deletion segregated with affected males and carrier females.⁶ A genome-wide parametric linkage analysis using 524 microsatellites was performed for a large consanguineous ID family with four affected indiv...