Genetic Test Results in Children Under 3 Years of Age Who Are at-Risk for Neurodevelopmental Disorders: An Update

Background:  A significant incidence of genetic aberrations has been documented in individuals with autism spectrum disorder and other neurodevelopmental disabilities (NDD) [Roberts et al., 2014]. The earlier these genetic alterations are identified, the sooner the individual can receive targeted interventions to reduce the impact of these disorders and improve outcomes. Several neurodevelopmental assessments have been designed to identify at-risk infants, including the Comprehensive Autism Spectrum Screening for Infants (CASS-i), which is meant to identify infants younger than 12 months who are at-risk for ASD/NDD [Samango-Sprouse et al., 2015].

Objectives:  To report the genetic aberrations in infants who fail the CASS-i . Specifically, we provide an update of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA; which was reported at the IMFAR in 2016) and report on newly identified findings from whole exome sequencing (WES) in the same patient cohort.

Methods:  Fourteen infants under the age of 3 years who failed the CASS-i were offered clinical CMA testing and research-based WES. CMA was done on a custom Affymetrix platform designed to optimize detection for genetic variants that underlie ASD as other NDD (FirstStep^Dx PLUS ®; Salt Lake City, UT). WES was performed using the AmpliSeq Exome target capture kit and Ion Torrent sequencers (ThermoFisher Scientific, Inc.) to an average read depth of 100X. Analysis of the sequence data was performed using the WuXi/NextCode Clinical Sequence Analysis pipeline (https://www.wuxinextcode.com/). Additional analysis of copy number variants and sequence variants using the method of Uddin et al. (2014) was used to identify novel genes possibly relevant to neurodevelopmental disorders.

Results:  Fourteen patients underwent clinical CMA testing and 4/14 had a reportable CMA finding (~28%) Thirteen patients underwent research WES; following variant filtration based on allele frequency and phenotypic relevance, roughly 40-50 variants requiring further evaluation were identified in each individual. A summary of these findings from both methodologies will be presented, along with specific examples to demonstrate the improved medical management that comes with a specific genetic diagnosis.

Conclusions:  Genetic testing is an important component in the clinical work-up of individuals with ASD/NDD. Of patients who fail early developmental screens, over 10% are expected to have a reportable finding on CMA and over 80% of are expected to have a reportable finding on WES. Clinicians should implement screening and genetic testing protocols to improve early detection and implement personalized medical management for patients with ASD/NDD. This often affords families both individualized and targeted treatment.