AUTISM SPECTRUM DISORDERS：THE ROLE OF GENETICS IN DIAGNOSIS AND TREATMENT（Edited by Stephen I. Deutsch and Maria R. Urbano）

AUTISM SPECTRUM DISORDERS: THE ROLE OF GENETICS IN DIAGNOSIS AND TREATMENT Edited by stephen l. Deutsch and maria R, Urbano INTECHWEB ORG

AUTISM SPECTRUM DISORDERS: THE ROLE OF GENETICS IN DIAGNOSIS AND TREATMENT Edited by Stephen I. Deutsch and Maria R. Urbano

Contents PrefaceⅨ Part 1 Early Recognition and Diagnosis 1 Chapter 1 Early Detection of Autism Spectrum Disorders 3 Jariya Chuthapisith and Nichara Ruangdaraganon Part 2 Nosology and Diagnostic Criteria: What Makes Sense and Can Genetics Help? 15 Chapter 2 Pervasive Developmental Disorder-not Otherwise Specified: Specifying and Differentiating 17 Koray Karabekiroglu Chapter 3 Autism and Genetic Syndromes 31 Willem Verhoeven, Jos Egger and lse Feenstra Part 3 Genetics and Pathophysiology of Autism Spectrum Disorders 49 Chapter 4 The Genetics of Autism Spectrum Disorders 51 John J.M. Connolly and Hakon Hakonarson Chapter 5 Genetic Heterogeneity of Autism Spectrum Disorders 65 Catherine Croft swanwick Eric C. Larsen and Sharmila banerjee-Basu Chapter 6 The Genetic Basis of Phenotypic Diversity: Autism as an Extreme Tail of a Complex Dimensional Trait 83 linji Ijichi, Naomi jichi, Yukina Jic Hisami Sameshima and Hirofumi morioka Chapter 7 A New Genetic Mechanism for Autism 103 Julie Gauthier and Guy A. Rouleau

Contents Preface IX Part 1 Early Recognition and Diagnosis 1 Chapter 1 Early Detection of Autism Spectrum Disorders 3 Jariya Chuthapisith and Nichara Ruangdaraganon Part 2 Nosology and Diagnostic Criteria: What Makes Sense and Can Genetics Help? 15 Chapter 2 Pervasive Developmental Disorder- not Otherwise Specified: Specifying and Differentiating 17 Koray Karabekiroglu Chapter 3 Autism and Genetic Syndromes 31 Willem Verhoeven, Jos Egger and Ilse Feenstra Part 3 Genetics and Pathophysiology of Autism Spectrum Disorders 49 Chapter 4 The Genetics of Autism Spectrum Disorders 51 John J.M. Connolly and Hakon Hakonarson Chapter 5 Genetic Heterogeneity of Autism Spectrum Disorders 65 Catherine Croft Swanwick, Eric C. Larsen and Sharmila Banerjee-Basu Chapter 6 The Genetic Basis of Phenotypic Diversity: Autism as an Extreme Tail of a Complex Dimensional Trait 83 Shinji Ijichi, Naomi Ijichi, Yukina Ijichi, Hisami Sameshima and Hirofumi Morioka Chapter 7 A New Genetic Mechanism for Autism 103 Julie Gauthier and Guy A. Rouleau

ontents Chapter 8 Common Genetic Etiologies and Biological Pathways Shared Between Autism Spectrum Disorders and Intellectual Disabilities 125 iana Kaufman Abdul noor Muhammad Ayub and John B. Vincent Part 4 Treatment and Genetic Counseling 159 Chapter 9 Microgenetic Approach to Therapy of girls with ASD 161 atarzyna Markiewicz and Bozydar L.J. Kaczmarek Chapter 10 Genetic Counseling in Autistic Phenotypes 181 Agnes Cristina Fett-Cc

VI Contents Chapter 8 Common Genetic Etiologies and Biological Pathways Shared Between Autism Spectrum Disorders and Intellectual Disabilities 125 Liana Kaufman, Abdul Noor, Muhammad Ayub and John B. Vincent Part 4 Treatment and Genetic Counseling 159 Chapter 9 Microgenetic Approach to Therapy of Girls with ASD 161 Katarzyna Markiewicz and Bożydar L.J. Kaczmarek Chapter 10 Genetic Counseling in Autistic Phenotypes 181 Agnes Cristina Fett-Conte

Preface The broadening of the definitional criteria of autism spectrum disorders(ASDs)and increased recognition of these syndromes have led to dramatic increases in their es- timated prevalence; prevalence estimates of ASDs in the USa are approximately 1 in 110 children with a three to four time greater male to female predominance. These disorders occur commonly as co-morbid conditions in several Mendelian genetic disorders due to the effects of a single major gene(e. g, tuberous sclerosis). Im- portantly, although these Mendelian disorders appear to be unrelated to each other, recent advances in bioinformatics and"network analyses"suggest that they may in deed be related to each other; the points of convergence can include development and architecture of the synapse, and early developmental events in neurogenesis, neuronal cell migration and synaptogenesis. Additionally, areas along the human genome are emerging as"hotspots"for microdeletions and microduplications, re- ferred to as Copy Number Variants(CNVs); the density of these CNVs may contrib- ute to increased risk of neurodevelopmental syndromes, including ASDs Remarka- bly, although the 1970s was focused on elucidating descriptive differences between ASDs and schizophrenia presenting in childhood; the emerging data on CNVs sug- gest that ASDs and schizophrenia, or at least their genetic mechanisms, may be more similar than initially appreciated. In any event, the genetic data are also suggesting molecular targets; for example, microdeletions at the 15q133 locus suggest that hap- insufficiency of a gene product of this locus (i.e., CHRNAZ, which codes for the a7 nicotinic acetylcholine receptor(a7 nAChR) subunit, may be causally associated with ASDs. Thus, selective nicotinic acetylcholine receptor agonist strategies should be explored for their potential therapeutic benefit. The high prevalence of these dis- orders, their impact on the identified affected patient and the unrecognized unaf fected family members(including sibs, accessibility of Array Comparative Genomic Hybridization screening technologies, elucidation of associations with candidate susceptibility genes, along with CNVs and complex genetics are raising profound ethical questions, heightening the challenges of genetic counseling. The staggering alleges of genetic cour (i.e, homologous maternal and paternal chromosomes may have different patterns of cytosine methylations and certain genetic disorders differ depending on genetic variations within one of the affected parer ntal chromosomes [e. g, Angelman and

Preface The broadening of the definitional criteria of autism spectrum disorders (ASDs) and increased recognition of these syndromes have led to dramatic increases in their es￾timated prevalence; prevalence estimates of ASDs in the USA are approximately 1 in 110 children with a three to four time greater male to female predominance. These disorders occur commonly as co-morbid conditions in several Mendelian genetic disorders due to the effects of a single major gene (e.g., tuberous sclerosis). Im￾portantly, although these Mendelian disorders appear to be unrelated to each other, recent advances in bioinformatics and “network analyses” suggest that they may in￾deed be related to each other; the points of convergence can include development and architecture of the synapse, and early developmental events in neurogenesis, neuronal cell migration and synaptogenesis. Additionally, areas along the human genome are emerging as “hotspots” for microdeletions and microduplications, re￾ferred to as Copy Number Variants (CNVs); the density of these CNVs may contrib￾ute to increased risk of neurodevelopmental syndromes, including ASDs. Remarka￾bly, although the 1970’s was focused on elucidating descriptive differences between ASDs and schizophrenia presenting in childhood; the emerging data on CNVs sug￾gest that ASDs and schizophrenia, or at least their genetic mechanisms, may be more similar than initially appreciated. In any event, the genetic data are also suggesting molecular targets; for example, microdeletions at the 15q13.3 locus suggest that hap￾loinsufficiency of a gene product of this locus (i.e., CHRNA7), which codes for the α7 nicotinic acetylcholine receptor (α7 nAChR) subunit, may be causally associated with ASDs. Thus, selective nicotinic acetylcholine receptor agonist strategies should be explored for their potential therapeutic benefit. The high prevalence of these dis￾orders, their impact on the identified affected patient and the unrecognized unaf￾fected family members (including sibs), accessibility of Array Comparative Genomic Hybridization screening technologies, elucidation of associations with candidate susceptibility genes, along with CNVs and complex genetics are raising profound ethical questions, heightening the challenges of genetic counseling. The staggering challenges of genetic counseling are further compounded by issues of imprinting (i.e., homologous maternal and paternal chromosomes may have different patterns of cytosine methylations and certain genetic disorders differ depending on genetic variations within one of the affected parental chromosomes [e.g., Angelman and

Prader-Willi syndromes)and variable "penetrance"(i.e, there is a broad array of possible phenotypes). The chapters contained in this book highlight some of these emerging issue Stephen I Deutsch, M D, Ph D and Maria R Urbano, M D Department of Psychiatry and Behavioral Sciences Eastern Virginia Medical School 825 Fairfax Avenue. suite 710 Norfolk, Virginia 23507-1912 USA

X Preface Prader-Willi syndromes]) and variable “penetrance” (i.e., there is a broad array of possible phenotypes). The chapters contained in this book highlight some of these emerging issues. Stephen I. Deutsch, M.D., Ph.D. and Maria R. Urbano, M.D. Department of Psychiatry and Behavioral Sciences Eastern Virginia Medical School 825 Fairfax Avenue, Suite 710 Norfolk, Virginia 23507-1912 USA