Diagnostic efficacy and new variants in isolated and complex autism spectrum disorder using molecular karyotyping
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Autism spectrum disorder (ASD) is a group of the neurodevelopment disorders presenting as an isolated ASD or more complex forms, where a broader clinical phenotype comprised of developmental delay and intellectual disability is present. Both the isolated and complex forms have a significant causal genetic component and submicroscopic genomic copy number variations (CNV) are the most common identifiable genetic factor in these patients. The data on microarray testing in ASD cohorts are still accumulating and novel loci are often identified; therefore, we aimed to evaluate the diagnostic efficacy of the method and the relevance of implementing it into routine genetic testing in ASD patients. A genome-wide CNV analysis using the Agilent microarrays was performed in a group of 150 individuals with an isolated or complex ASD. Altogether, 11 (7.3%) pathogenic CNVs and 15 (10.0%) variants of unknown significance (VOUS) were identified, with the highest proportion of pathogenic CNVs in the subgroup of the complex ASD patients (14.3%). An interesting case of previously unreported partial UPF3B gene deletion was identified among the pathogenic CNVs. Among the CNVs with unknown significance, four VOUS involved genes with possible correlation to ASD, namely genes SNTG2, PARK2, CADPS2 and NLGN4X. The diagnostic efficacy of aCGH in our cohort was comparable with those of the previously reported and identified an important proportion of genetic ASD cases. Despite the continuum of published studies on the CNV testing in ASD cohorts, a considerable number of VOUS CNVs is still being identified, namely 10.0% in our study.
KeywordsAutism spectrum disorders ASD Microarrays Molecular karyotyping UPF3B gene Genetics of autism
array comparative genomic hybridization
autism spectrum disorder(s)
copy number variant
variant of unknown significance
LL, MV, SB, BGS, DO and MJV carried out the clinical evaluation and provided the clinical genetic consultations to patients. LL and PR analysed and interpreted the data. LL, PR, MV and BP drafted the manuscript. SB, BGS, MJV and DO critically revised the final manuscript. All authors read and approved the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
The study was approved by the National Ethical Review Board in Ljubljana, Slovenia (0120-288/2016-2). All participants (their legal representatives) signed a written, informed consent.
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