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
Tesi di Dottorato
Data di Pubblicazione:
2013
Citazione:
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 / C. Castronovo ; supervisore: P. Finelli ; tutor: M. T. Bonati ; coordinatore: M. Locati. UNIVERSITA' DEGLI STUDI DI MILANO, 2013 Mar 25. 25. ciclo, Anno Accademico 2012. [10.13130/castronovo-chiara_phd2013-03-25].
Abstract:
Autistic behaviors were independently identified as recognizable syndromes in the early 20th century by Heller and, subsequently, by Kanner and Asperger. The autism diagnosis spans a broad continuum of what are collectively known as Autism Spectrum Disorders (ASDs) or Pervasive Developmental Disorders (PDDs). ASDs include several conditions, namely full-syndrome autism (Autistic Disorder or Idiopathic Autism), Childhood Disintegrative Disorder, Asperger Syndrome (AS) and Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS). The latest estimates put the population prevalence of ASDs at approximately 1 in 110. Furthermore, ASDs show a 4:1 male to female gender bias, which may rise to 11:1 when considering Asperger disorder. Although heterogeneous, ASDs 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. Symptoms of ASDs usually begin in early childhood with evidence of delayed development before age 3 years.
The etiology of ASDs 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 ASDs. Twin and family studies have, indeed, established the preponderant genetic basis of autism and indicate that the heritability of autism is over 90%, which is the highest heritability value so far associated with a neuropsychiatric disorder. The genetic causes of ASDs can be classified as: (1) ASD-related monogenic syndromes; (2) rare chromosomal abnormalities; (3) rare copy number variations (CNVs); (4) rare gene mutations; (5) common genetic variants.
Recently, submicroscopic CNVs, de novo and inherited, are emerging as an important category of genetic risk for ASDs with a different impact depending on the type of CNV identified. Screening for CNVs by means of array CGH and SNP array technologies has proven to be one of the more successful strategies for the discovery of ASD candidate loci over the past five years. Furthermore, the same or overlapping CNVs are being identified as risk factors across a few neurodevelopmental disorders, indicating that some ASD loci are likely pleiotropic with variable expressivity. The increased resolution of the array-based approaches suggests that the proportion of ASD cases (both idiopathic and syndromic) that may be ultimately attributed to a rare structural variant is around 10-20%. The de novo CNV rate in ASDs is roughly three to seven times than that in controls and has been reported to be higher in simplex (low-risk) compared to multiplex families (high-risk). Furthermore, CNV screening gave rise to a paradigm shift away from a common variant model of ASD genetic architecture (based on low penetrating variants) to one suggesting a role for multiple rare and distinct genetic risk factors (with a higher penetrance), known as oligogenic heterozygosity model, which does not exclude, however, a modulation of the phenotype by common susceptibility genetic variants.
We collected a series of 115 patients (92 males and 23 females) who were diagnosed with ASDs: 41 with idiopathic Autism, 46 with PDD-NOS, 15 with Syndromic Autism, 8 with High-Functioning Autism, and 4 with Asperger syndrome. Genomic DNA from all patients was used to perform array CGH analysis (Agilent Technology) in order to detect CNVs. In particular, 18 patients were analyzed at a lower resolution (44K or 60K Kits) and 97 at a higher resolution (244K Kit). In the event of detection of rare CNVs, if possible, patients’ parents were analyzed to characterize the origin of the unbalanced m
Tipologia IRIS:
Tesi di dottorato
Keywords:
autism spectrum disorders ; copy number variations ; array CGH
Elenco autori:
C. Castronovo
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