Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test

Genes (Basel). 2021 Apr 12;12(4):560. doi: 10.3390/genes12040560.


Autism spectrum disorder (ASD) is a prevalent and extremely heterogeneous neurodevelopmental disorder (NDD) with a strong genetic component. In recent years, the clinical relevance of de novo mutations to the aetiology of ASD has been demonstrated. Current guidelines recommend chromosomal microarray (CMA) and a FMR1 testing as first-tier tests, but there is increasing evidence that support the use of NGS for the diagnosis of NDDs. Specifically in ASD, it has not been extensively evaluated and, thus, we performed and compared the clinical utility of CMA, FMR1 testing, and/or whole exome sequencing (WES) in a cohort of 343 ASD patients. We achieved a global diagnostic rate of 12.8% (44/343), the majority of them being characterised by WES (33/44; 75%) compared to CMA (9/44; 20.4%) or FMR1 testing (2/44; 4.5%). Taking into account the age at which genetic testing was carried out, we identified a causal genetic alteration in 22.5% (37/164) of patients over 5 years old, but only in 3.9% (7/179) of patients under this age. Our data evidence the higher diagnostic power of WES compared to CMA in the study of ASD and support the implementation of WES as a first-tier test for the genetic diagnosis of this disorder, when there is no suspicion of fragile X syndrome.

Keywords: FMR1 testing; autism spectrum disorder; chromosomal microarray; copy number variations; diagnostic yield; exome sequencing.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age Factors
  • Algorithms
  • Autism Spectrum Disorder / diagnosis*
  • Autism Spectrum Disorder / genetics
  • Child
  • Child, Preschool
  • Chromosomes, Human / genetics
  • Early Diagnosis
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Genetic Testing
  • Humans
  • Infant
  • Male
  • Oligonucleotide Array Sequence Analysis / methods*
  • Sensitivity and Specificity
  • Whole Exome Sequencing / methods*
  • Young Adult


  • FMR1 protein, human
  • Fragile X Mental Retardation Protein