To evaluate the clinical utility of including FMR1 repeat analysis as a first-tier genetic test for children with autism spectrum disorder (ASD), global developmental delay (GDD) and/or intellectual disability (ID).

Guidelines for evaluating children with ASD/GDD/ID recommend FMR1 repeat analysis and chromosomal microarray (CMA) as first-tier tests. However, recent studies show a low diagnostic yield of FMR1 testing for individuals without a clinical suspicion of Fragile X syndrome.

A retrospective study to evaluate the positive diagnostic rate (PDR) of first-tier genetic tests (FMR1 and CMA) compared to a second-tier test, Autism/ID Xpanded panel (sequencing of >2300 genes associated with ASD/ID).  Study includes 523 unselected patients (145 females; 378 males) with ASD/GDD/ID referred to our laboratory for genetic testing. 

Positive FMR1 full expansions were identified in 0.6% (3/523) of cases and all positive results were identified in males. CMA testing identified causative copy number variants (CNVs) in 5.5% (29/523) of cases. Seventy-two percent of individuals (n=375) proceeded to second-tier testing with the Autism/ID Xpanded panel. The PDR of the panel was 9.6% (36/375). Five positive CMA cases continued with the Xpanded panel; all five CNVs were identified by next-generation sequencing (NGS) along with a second causative variant identified by sequencing in one individual.

Our data demonstrates a low diagnostic yield of FMR1 repeat testing in the general ASD/GDD/ID population and especially for females. These data support the growing literature that FMR1 testing is not an effective first-tier test despite the relatively low cost. CMA yielded a higher PDR and the Autism/ID Xpanded panel had the highest diagnostic yield (~10%). CMA as a first-tier test is more cost effective currently, however, as technology improves, the detection of CNVs along with sequence variants from NGS data will likely become the more cost-effective, higher yield first-tier genetic test for patients with ASD/GDD/ID.