Diversity of molecular karyotypes of 234 pediatric patients with autism spectrum disorder in chromosomal microarray analysis.

backgroundAutism spectrum disorder (ASD) is a group of neurodevelopmental disorders that include deficits in social communication, maintaining relationships, and repetitive behaviors. In 25-35% of ASD cases, the genetic etiology (high-penetrance variants and copy number variations - CNVs) can be identified through whole-exome sequencing or chromosomal microarray analysis (CMA). CMA is a method dedicated to detecting submicroscopic chromosomal imbalances. The study aims to analyze CMA results in children with ASD.

methodsCMA results (CytoScan 750 K and XON, GRCh37/hg19 reference genome) from 234 children with ASD, diagnosed between 2012 and 2024 at Prof. Antoni Gębala Children's Hospital of Lublin, were analyzed retrospectively. Statistical analyses were conducted with α = 0.05 to determine significance. Hierarchical clustering on principal components was applied using Ward's linkage with the D2 metric, assuming Euclidean distance and no predefined number of clusters.

resultsNormal molecular karyotype was found in 58.97% of patients. In the abnormal CMA results, the most common were single duplications (14.53%) and single deletions (11.97%). Multiple CNVs occurred in 12.82% of patients. The diagnostic yield for pathogenic and likely pathogenic CNVs was 8.55%. Duplication of the 15q13.3 region was noted 4 times (OTUD7A, CHRNA7). Duplications of the following regions: 1p36.32 (ACTRT2, PRDM16), 3q22.1, 5q14.1, 9p24.1, 9p24.3, 11q23.3 (KMT2A, TMEM25), 12q24.13q24.21 (RBM19), 12q24.33 (TMEM132D), 15q11.2 (NIPA2, NIPA1, CYFIP1, TUBGCP5), 22q11.21 (RIMBP3C, RIMBP3B, HIC2), and 7q33, 22q12.3, Yq11.23 deletions (DAZ3, DAZ2) were noted 2 times each. Functions of the assessed genes were concerned with neurodevelopment, neurotransmission, metabolism, immune system, transcription, translation, cell cycle regulation, cell signaling and transport, apoptosis, detoxification, mitochondrial, and cytoskeletal functions. Hierarchical clustering enables the separation of three subgroups: with variants of uncertain significance, with high proportions of variants of uncertain significance and sparse pathogenic fractions, and with pathogenic dominance. Our findings replicate previously established ASD associated CNV loci in an independent clinical cohort.

conclusionsThe study indicated the noticeable heterogeneity of the genetic profile of pediatric patients with ASD. The availability of CMA has significantly increased the percentage of patients in whom the genetic etiology of ASD has been established. There is a need for further analysis of point mutations in next-generation sequencing and investigation of epigenetic changes in a wider research group. CLINICAL TRIAL NUMBER: Not applicable.