Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders

Abstract

Copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) significantly contribute to understanding the etiology of autism spectrum disorder (ASD) and other related conditions. In recognition of the value of CMA testing and its impact on medical management, CMA is in medical guidelines as a first-tier test in the evaluation of children with these disorders. As CMA becomes adopted into routine care for these patients, it becomes increasingly important to report these clinical findings. This study summarizes the results of over 4 years of CMA testing by a CLIA-certified clinical testing laboratory. Using a 2.8 million probe microarray optimized for the detection of CNVs associated with neurodevelopmental disorders, we report an overall CNV detection rate of 28.1% in 10,351 consecutive patients, which rises to nearly 33% in cases without ASD, with only developmental delay/intellectual disability (DD/ID) and/or multiple congenital anomalies (MCA). The overall detection rate for individuals with ASD is also significant at 24.4%. The detection rate and pathogenic yield of CMA vary significantly with the indications for testing, age, and gender, as well as the specialty of the ordering doctor. We note discrete differences in the most common recurrent CNVs found in individuals with or without a diagnosis of ASD.

Clinical and genetic aspects of the 15q11.2 BP1–BP2 microdeletion disorder

“…As discussed earlier, multiple laboratory methods can identify the microdeletion including FISH (Butler et al ; Butler ), methylation specific‐multiplex ligation‐dependent problem amplification (MS‐MLPA) (Bittel et al ; Henkhaus et al ) and microarray analyses (Roberts et al ; Butler et al ; Ho et al ). Genotyping of appropriate informative DNA markers within the genomic region can also be used to identify the 15q11.2 BP1–BP2 microdeletion in at‐risk family members.…”

“…This cytogenetic region when disturbed is associated with autism and other behaviour, learning or neurodevelopmental problems and one of the most common cytogenetic regions harbouring genes for these clinical problems supported by a recent study of 10 351 consecutive patients (7422 M; 2929 F or 2.5:1 sex ratio) presenting for genetic services and microarray analysis (Ho et al ). They reported that 5694 patients had ‘any ASD’ designation as the sole testing indicator or in combination with any other testing indication.…”

GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia

“…A large number of autism-specific CNVs have been found but with low recurrence (<1%) and they show a high level of genetic heterogeneity. For example, when the 15q11.2 BP1–BP2 region or 15q13.3 band contains a deletion or duplication in patients, then autism or a variety of neuropsychiatric traits including schizophrenia are identified [3,17,18,19]. Gene expression disturbances were found using postmortem cortical brain tissue from patients with autism, schizophrenia and bipolar disorder and they have shown a high correlation between the transcriptomes of ASD and schizophrenia, but not in BPD [5].…”

Reciprocal White Matter Changes Associated With Copy Number Variation at 15q11.2 BP1-BP2: A Diffusion Tensor Imaging Study

“…Moreover, recent ultra high-resolution chromosomal microarray analyses report the 15q11.2 BP1-BP2 deletion as the most frequent finding in those with only ASD or with ASD combined with intellectual disability and congenital anomalies (10). The reciprocal duplication has also been associated with increased risk for ASD (11), although its significance is still unclear (8).…”