Abstract
Since the introduction of high-resolution microarray technologies, it has become apparent that structural chromosomal rearrangements can lead to a wide variety of clinical manifestations, including developmental delay/intellectual disability (DD/ID). It has been shown previously that the diagnostic yield of genome-wide array-based identification of submicroscopic alterations in patients with ID varies widely and depends on the patient selection criteria. More attempts have recently been made to define the phenotypic clues of pathogenic copy number variants (CNVs). The aim of this study was to investigate a well-phenotyped cohort of patients with DD/ID and determine whether certain clinical features may serve as indicators for pathogenic CNVs. A retrospective analysis was conducted for patients with DD/ID (n = 211) who were tested using genome-wide chromosomal microarray technologies and a review of the clinical data was performed. Pathogenic CNVs were detected in 29 patients. In comparison with individuals who had normal molecular karyotyping results (n = 182), malformations of the musculoskeletal system; congenital malformations of the CNS (particularly hydrocephalus and congenital malformations of the corpus callosum); minor anomalies of the eye, face, and neck subgroup (particularly downward-slanting palpebral fissures, minor anomalies of the ear, and micrognathia); brachydactyly; and umbilical hernia were more common in patients with chromosomal alterations. A multivariate logistic regression analysis allowed the identification of three independent pathogenic CNV predictors: congenital malformations of the corpus callosum, minor anomalies of the ear, and brachydactyly. Insights into the chromosomal phenotype may help to increase the diagnostic yield of microarray technologies and sharpen the distinction between chromosomal alterations and other conditions.
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Acknowledgement
We would like to thank to the clinical geneticists of the Centre for Medical Genetics at Vilnius University Hospital Santariškių Clinics and our partners from the Cyprus Institute of Neurology and Genetics, Alma Mater Studiorum (University of Bologna), and University of Tartu for collaboration. The research leading to these results was funded by the European Community’s Seventh Framework Programme [FP7/2007–2013] under grant agreement no. 223692, CHERISH project, the Research Council of Lithuania National Research Programme “Chronic Non-Infectious Diseases” under grant agreement no. LIG-12/2010, the PROGENET project, and the Lithuanian–Swiss cooperation program to reduce economic and social disparities within the enlarged European Union under project agreement no. CH-3-ŠMM-01/04, UNIGENE project.
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Preiksaitiene, E., Molytė, A., Kasnauskiene, J. et al. Considering specific clinical features as evidence of pathogenic copy number variants. J Appl Genetics 55, 189–196 (2014). https://doi.org/10.1007/s13353-014-0197-x
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DOI: https://doi.org/10.1007/s13353-014-0197-x