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Università Degli Studi Di Milano UNIVERSITÀ DEGLI STUDI DI MILANO DOTTORATO IN PATOLOGIA E NEUROPATOLOGIA SPERIMENTALI Dipartimento di Biotecnologie Mediche e Medicina Traslazionale Curriculum Genetico/XXV Ciclo RARE DE NOVO AND TRANSMITTED COPY NUMBER VARIATIONS IN AUTISM SPECTRUM DISORDERS: IMPLICATIONS FOR FUNCTIONAL NETWORKS OF GENES INVOLVED IN NEUROGENESIS, NEURONAL METABOLISM, SYNAPTIC FUNCTION, NEUROIMMUNITY, INTRACELLULAR SIGNALING AND CHROMATIN REMODELING Settore scientifico disciplinare: MED/03 Tesi di Dottorato di: Dott.ssa Chiara CASTRONOVO Matr. R08592 Docente di riferimento: Prof.ssa Palma FINELLI Tutor: Dott.ssa Maria Teresa BONATI Coordinatore del Dottorato: Prof. Massimo LOCATI Anno Accademico 2011/2012 1 To my husband 2 Index Introduction page 4 1. Autism Spectrum Disorders (ASD) page 5 1.1 Classification and clinical diagnosis page 5 1.2 Etiopathogenesis page 6 1.2.1 Genetic architecture in Autism Spectrum Disorders page 6 1.2.2 Mode of inheritance page 11 1.2.3 Mitochondrial abnormalities in Autism Spectrum Disorders page 12 1.2.4 Immune dysfunctions in Autism Spectrum Disorders page 14 1.2.5 Environmental factors page 18 2. Copy number variations (CNVs) in human genome page 20 2.1 Copy number variations in Autism Spectrum Disorders page 21 3. Neurobiology of Autism Spectrum Disorders page 25 3.1 Neuroanatomical abnormalities in ASD page 25 3.2 ASDs represent a “synaptopathy” page 27 Patients and Methods page 36 4.1 Patients page 37 4.2 Molecular karyotyping by means of array-based Comparative Genomic Hybridization (array CGH) analysis page 39 4.2.1 Extraction of genomic DNA (gDNA) from peripheral blood page 39 4.2.2 gDNA enzymatic restriction digestion page 39 4.2.3 Fluorescent Labeling of DNA by Agilent Genomic DNA Labeling Kit PLUS page 41 4.2.4 Clean-up of Labeled Genomic DNA page 42 4.2.5 Preparation of Labeled Genomic DNA for Hybridization page 42 4.3 Copy Number Variant analysis page 44 Results page 46 5.1 Identification and classification of rare CNVs page 47 Table 3 page 50 5.2. Analysis of the gene content of the identified rare CNVs page 57 Table 4 page 59 Table 4.1 page 85 Discussion page 153 6.1 Analysis of the identified rare CNVs: implication for genotype-phenotype correlation page 154 6.2 Identification of functional networks of genes potentially implicated in ASD page 161 References page 187 Acknowledgements page 243 3 INTRODUCTION 4 1. Autism Spectrum Disorders (ASD) 1.1 Classification and clinical diagnosis Autistic behaviors were independently identified as recognizable syndromes in the early 20th century by Heller [Heller, 1908] and, subsequently, by Kanner [Kanner, 1943] and Asperger [Asperger, 1944]. In particular, Prof. Kanner described autism in 1943 in 11 children manifesting withdrawal from human contact as early as age 1 year postulating origins in prenatal life [Kanner, 1943]. In the Diagnostic and Statistical Manual of Mental Disorders IV-Text Revised (DSM-IV- TR) [Task Force on DSM-IV, 2000] the autism diagnosis spans a broad continuum of what are collectively known as Autism Spectrum Disorders (ASD) or Pervasive Developmental Disorders (PDD). ASD include several conditions, namely full-syndrome autism (Autistic Disorder or Idiopathic Autism) [MIM 209850], Childhood Disintegrative Disorder, Asperger Syndrome (AS) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) [Task Force on DSM-IV, 2000]. The latest estimates put the population prevalence of ASD at approximately 1 in 110 [Autism and Developmental Disabilities Monitoring Network, 2009]. Incidence appears to be independent of ancestry and demographics, when similar rates being found on a global scale when the same diagnostic tools are used [Fombonne, 2009]. ASD show a 4:1 male to female gender bias, which may rise to 11:1 when considering Asperger disorder [Gillberg et al., 2006]. Although heterogeneous, ASD are united by a combination of three core behavior symptoms: a) impaired language and communication; b) deficiencies in social interaction; c) restricted interest and repetitive stereotypic behavior [Task Force on DSM-IV, 2000]. Symptoms of ASD usually begin in early childhood with evidence of delayed development before age 3 years, although prospective studies of children at higher risk have shown that deficits in social interaction and communication may be starting in the first 6-12 months of life [Pizzarelli and Cherubini, 2011]. The fully-autistic patients show impairments in all the three areas of behavior previously described, whereas AS patients have deficits in social interaction and behavior but normal cognitive development and language skills. A diagnosis of PDD-NOS is instead placed in those patients who meet the diagnostic criteria for autism, but with a later onset, or in those patients who show two out of the three core behavior symptoms [Task Force on DSM-IV, 2000]. Furthermore, about 50-70% of children with autism are identified as intellectually disabled by nonverbal IQ testing and approximately 25% develop seizures [Baird et al., 2006; Tuchman and Rapin, 2002]. Autism can be considered complex due to the presence of dysmorphic features (25-30%) and/or microcephaly (5-15%) or macrocephaly (30%), or essential (i.e., absence of physical abnormalities and microcephaly). 5 Other common pathological disturbances may be present including anxiety, sensorial abnormalities, gait and motor disturbances, sleep disturbances and comorbidity with psychiatric disorders such as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD) and mood disorder [Geschwind, 2009]. Rating scales helpful in establishing the diagnosis are Autism Diagnostic Interview-Revised (ADI- R) and the Autism Diagnostic Observation Schedule (ADOS) in combination with clinical presentation [Lord et al., 1989, 1994]. 1.2 Etiopathogenesis 1.2.1 Genetic architecture in Autism Spectrum Disorders The etiology of ASD is complex and encompasses the roles of genes, the mitochondria, the environment, and the immune system. However, there is strong evidence for the importance of complex genetic factors comprised of different form of genetic variations in the etiology of ASD. Twin and family studies have, indeed, established the preponderant genetic basis of autism and indicate that the heritability of autism is over 90% [Abrahams e Geschwind, 2008; Freitag, 2007; Monaco and Bailey 2001; Muhle et al., 2004; Persico e Bourgeron, 2006], which is the highest heritability value so far associated with a neuropsychiatric disorder [Schaaf and Zoghbi, 2011]. Furthermore, the recurrence risk for ASD varies by gender for the second child to be affected (4% if the first child affected is a female and 7% if a male), whereas the recurrence rate increases to 25- 30% if the second child is also diagnosed with ASD [Constantino et al., 2010; Ozonoff et al., 2011; Rosenberg et al., 2011]. The genetic causes of ASD can be classified as follows (Figure 1): 1) ASD-related monogenic syndromes; 2) rare chromosomal abnormalities; 3) rare copy number variations (CNVs); 4) rare gene mutations; 5) common genetic variants. 1) Approximately 10% of patients with ASD have an identifiable Mendelian condition or genetic syndrome (Fig. 1) [Devlin and Scherer, 2012]. This means that these patients are characterized by a complex phenotypic picture, showing autistic traits as well as craniofacial dysmorphism and/or congenital malformations. Unlike idiopathic autism, syndromic ASD have a sex ratio M:F of 1:1. Among these syndromes the most frequent are Fragile X syndrome (~1-2% of ASD cases), Tuberous sclerosis (~1%), PTEN macrocephaly syndrome (1%), and Rett syndrome (~0.5-1%). In detail, Fragile X syndrome is caused by expansion of the CGG trinucleotide repeat in the FMR1 gene to the full mutation size of 200 or more CGG repeats. Molecular studies indicate that FMR1 6 may cause the autism phenotype via two mechanisms: RNA toxicity to the neurons and gene silencing that affects neuronal connectivity [Hagerman et al., 2008; Handa et al., 2005; Schenck et al., 2003]. The PTEN (phosphatase and tensin homolog) gene was initially described as a tumor suppressor gene associated with a broad group of disorders referred to as PTEN hamartoma tumor syndrome. More recently, PTEN mutations have been associated with autism and macrocephaly [Butler et al., 2005; Buxbaum et al., 2007; Delatycki et al., 2003; Parisi et al., 2001; Zori et al., 1998], and PTEN is recognized to play an important role in brain development, neuronal survival and synaptic plasticity. Rett syndrome was initially classified by the DSM-IV as a pervasive developmental disorder (PDD) and it is the only PDD for which a specific genetic etiology has been identified [Amir et al., 1999]. Ninety-six percent of individuals with classic Rett syndrome have mutations in the X-linked MECP2 gene [Moretti and Zoghbi, 2006] and MECP2 mutations have been reported in approximately 1% of children diagnosed with autism [Lintas and Persico, 2009; Moretti and Zoghbi, 2006]. Evidence of variable expression of MeCP2 in the brains of individuals with both autism and Rett syndrome and evidence that MeCP2 deficiency can reduce expression of the genes UBE3A and GABRB3, which are implicated in autism, indicate some causal relationship between the two disorders [Samaco et al., 2004, 2005]. Other rare syndromes associated with ASD (<1%) are, for example, Neurofibromatosis type I, Sotos, Timothy, and Joubert syndromes. Moreover, in a recent review over than 103 disease genes were identified among subjects with ASD or autistic behavior [Betancur,
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