Objective:

To determine the current sensitivity of trio whole genome sequencing (trio-WGS) in autism.

Background:

The last decade has seen dramatic improvements in the proportion of the genome clinically sequenced (e.g., < 1% to > 99%), accuracy, bioinformatic tools, and variant databases. Rapidly shifting methodologies have complicated sensitivity measurements. Additionally, the current literature is almost entirely from academic research centers, and sensitivity in independent organizations is unclear.

Design/Methods:

NeurAbilities Healthcare is an independent organization specializing in neurodevelopmental disorders. As part of our routine clinical practice, we analyzed the raw DNA sequencing files on the Variantyx bioinformatics platform for the last 20 autism patients in 2022 who had trio-WGS. Since the adoption of upgraded bioinformatics in late 2021, methodology has been essentially static, allowing for measurement of current testing sensitivity.

Results:

Monogenic causal diagnoses (MCD) were provided in 15/20 (75%) cases, including 11 heterozygous de novo, 2 X-linked and 2 autosomal recessive. Patients with moderate-to-profound intellectual disability (11/12 v. 4/8, P=0.011) and those without tics (13/14 v. 2/6, P=0.014) were statistically more likely to obtain a causal diagnosis. Only 7/15 (47%) of MCD cases had the variant listed on the laboratory report. The “missed” cases included genes with ≤4 reported families (THOC2, SLC41A2) and with no prior case reports (TRPM2, PGAM5, MTMR4, GRIK1, CD177). Not all de novo variants were labelled as MCD; each of those labeled were in genes previously associated with autism. Of the five cases without an MCD, three had variants likely/potentially related to disease. Overall, 16/20 (80%) of cases had treatment recommendation(s) based on DNA.

Conclusions:

Our results demonstrate high yield of trio-WGS for revealing molecular diagnoses in autism that is greatly enhanced by re-analyzing DNA sequencing files. Many are de novo and represent un/under-published conditions that are not within the scope of reporting by clinical laboratories.