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Title: Clinical relevance of copy number variations detected by array-coh in six patients with unexplained non-syndromic intellectual disability
Authors: Ferraz, Ana Isabel Borges 
Orientador: Oliveira, Guiomar
Maciel, Patrícia
Keywords: Génotipo; Fénotipo; Deficiência intelectual
Issue Date: Mar-2012
Abstract: Intellectual disability (ID) represents a health problem of great relevance for the public health services and for the families and is one of the most common neurodevelopmental disorders, affecting 1 to 3% of children. Epidemiological studies show that genetic mutations contribute in about 15% to the etiology in milder forms. When ID is present with other symptoms or physical features, the identification of the causative effect is not so difficult to educe. On the contrary, ID can be present as a sole clinical feature or with additionally subtle symptoms, sometimes difficult to diagnose. In about half the cases of ID, despite a thorough medical history and laboratory investigation widened, the etiology remains unknown. In recent years, submicroscopic structural variations in copy number, known as copy number variations (CNVs) of a specific chromosomal region, have been implicated in the etiology of ID. Novel high resolution, whole genome technologies, such as array-based comparative genomic hybridization (array- CGH), improve the detection rate of submicroscopic chromosomal aberrations, allowing the re-investigation of cases where conventional cytogenetics failed to detect any mutation. However, the application of this contemporary molecular technology has also resulted in the discovery of widespread CNVs in human genome and understanding the clinical significance of these alterations on phenotype variation has been a real challenge, especially in non-syndromic ID (NS-ID). Although it has already contributed to the etiological classification of a large portion of ID patients, sometimes it can be difficult to pinpoint for certain that the alterations found are the cause of the phenotype, especially in NS-ID cases. With the rapid discovery of the genetic causes underlying NS-ID and the pathways and processes involved in neurodevelopment and cognition, this will inevitably feedback into clinical diagnostics of these forms of ID. The aim of this study is to use array-CGH for the screening of patients with “idiopathic” ID, in order to detect submicroscopic copy number changes and correlate them with the phenotype. In this study, a sample of 42 children monitored at the Neurodevelopmental and Autistic Unit of the Carmona da Mota Pediatric Hospital of Coimbra, with the diagnosis of non-syndromic ID (NS-ID) or with minor dysmorphisms based on clinical observation and implementation of gold standard scales for ID diagnosis, are being analyzed by array-CGH (17 Mb resolution level) in Life and Health Sciences Research Institute (ICVS) from Minho´s University. According to available laboratorial results, we selected six patients from the sample of 42 to analyze whether the high resolution, genomewide, microarray-based, copy number screening would allow the identification of small rearrangements not detected by other techniques which could be the explanation for their NS-ID or learning disorders. In these six patients, we found two likely pathogenic chromosomal alterations, the duplications in Xp11.22 and 2q11.2 chromosomes. Based on current evidence, other potential pathogenic alterations were found and in many others it was not possible to assess their clinical significance. During the interpretation of the clinical relevance of CNVs, many generalizations are made, as regards to the type of the event, size, gene content and inheritance. Sometimes this can lead to the exclusion of CNVs that could have a real impact on the phenotype. Current evidence shows that small duplications can have a role in the phenotype and even alterations that do not encompass any genes may affect the genetic expression. Moreover, environmental factors may also have an impact on the way genotype is expressed. This study underlines the importance of a new integrated and multidimensional model for the interpretation of alterations found by array-CGH, specially in cases of NS-ID.
Description: Trabalho final de mestrado integrado em Medicina, área de Pediatria, apresentado á Faculdade de Medicina da Universidade de Coimbra
Rights: openAccess
Appears in Collections:FMUC Medicina - Teses de Mestrado
UC - Dissertações de Mestrado

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