High-Resolution Chromosomal Microarray Analysis in Children with Speech & Language Delay: Genetic Findings & Clinical Relevance

Background:  Chromosomal microarray analysis (CMA) is a whole-genome genetic interrogation that may identify a cause for neurodevelopmental challenges such as autism spectrum disorder (ASD), developmental delay (DD) and intellectual disabilities (ID). For this reason, CMA is recommended in medical guidelines as first-tier testing in the clinical evaluation of children with ASD, DD and ID. Because early diagnosis of ASD is critical for treatment and improved outcomes, screening methods continue to be developed and evaluated. For example, early recognition of speech & language (S&L) delay may identify children who are at risk for ASD sooner than is currently possible. S&L delay is often an early sign of a neurodevelopmental disorder in children who are eventually diagnosed with ASD.

Objectives:  We wanted to determine the prevalence of genetic causes, namely copy number variants (CNVs), in children who have S&L delay as an indication for their clinical testing. We could then determine whether CNVs were associated with increased risk for ASD.

Methods: We studied the CMA results of 10,351 patients for whom CMA was ordered as part of a clinical work-up for S&L delay, ASD, DD, ID and other indications using Lineagen’s FirstStep^Dx PLUS CMA service from 10/29/2010 through 09/30/16. T-test and chi-square analyses were used to determine whether there were significant differences in the average age at testing and detection rate, respectively, between the study groups.

Results: Our results show that children with S&L delay are being referred for genetic testing at an earlier age (~ 2 years younger) than children without S&L delay who have other testing indications. In addition, children with S&L delay have the same rate of pathogenic findings as children with other indications for testing such as ASD. Females with S&L delay have a significantly higher rate of pathogenic findings (12.8%) than males with S&L delay (7.7%). Neurologists order CMA in children with S&L delay more often than other specialists or pediatricians. Comparison of the most common genetic diagnoses shows that the causes of S&L delay vs. other indications are different and that there are important changes in clinical management associated with these genetic disorders.

Conclusions: Children with S&L delay often have an identifiable genetic cause for their clinical challenges. The rate of abnormal genetic findings is the same or greater than in children with other guideline recommended clinical indications (ex: ASD). We do not know whether children with S&L delay who were referred for testing went on to develop ASD. However, this study is important because it suggests that CMA, which can be done at any age upon recognition of S&L delay, may offer objective information that leads to earlier identification of ASD than is currently possible. These findings underscore the importance of CMA as soon as risk factors or developmental delays are identified.