PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
High Sensitivity for Detection of Primary Diagnostic Variants in Autism, Including De Novo Variants, with Trio Whole Genome Sequencing and Data Reanalysis
Version 1
: Received: 9 August 2023 / Approved: 14 August 2023 / Online: 14 August 2023 (09:36:37 CEST)
Version 2
: Received: 29 September 2023 / Approved: 9 October 2023 / Online: 10 October 2023 (05:00:59 CEST)
How to cite:
Bar, O.; Vahey, E.; Mintz, M.; Frye, R.E.; Boles, R.G. High Sensitivity for Detection of Primary Diagnostic Variants in Autism, Including De Novo Variants, with Trio Whole Genome Sequencing and Data Reanalysis. Preprints2023, 2023081002. https://doi.org/10.20944/preprints202308.1002.v1
Bar, O.; Vahey, E.; Mintz, M.; Frye, R.E.; Boles, R.G. High Sensitivity for Detection of Primary Diagnostic Variants in Autism, Including De Novo Variants, with Trio Whole Genome Sequencing and Data Reanalysis. Preprints 2023, 2023081002. https://doi.org/10.20944/preprints202308.1002.v1
Bar, O.; Vahey, E.; Mintz, M.; Frye, R.E.; Boles, R.G. High Sensitivity for Detection of Primary Diagnostic Variants in Autism, Including De Novo Variants, with Trio Whole Genome Sequencing and Data Reanalysis. Preprints2023, 2023081002. https://doi.org/10.20944/preprints202308.1002.v1
APA Style
Bar, O., Vahey, E., Mintz, M., Frye, R.E., & Boles, R.G. (2023). High Sensitivity for Detection of Primary Diagnostic Variants in Autism, Including De Novo Variants, with Trio Whole Genome Sequencing and Data Reanalysis. Preprints. https://doi.org/10.20944/preprints202308.1002.v1
Chicago/Turabian Style
Bar, O., Richard E. Frye and Richard G. Boles. 2023 "High Sensitivity for Detection of Primary Diagnostic Variants in Autism, Including De Novo Variants, with Trio Whole Genome Sequencing and Data Reanalysis" Preprints. https://doi.org/10.20944/preprints202308.1002.v1
Abstract
Autism spectrum disorder (ASD) is a common condition with lifelong implications and a strong hereditary component suggesting genetic underpinnings. The last decade has seen dramatic improvements in DNA sequencing, bioinformatics, and databases.
We analyzed the raw DNA sequencing files on the Variantyx® (Framingham, MA, USA) bioinformatics platform for the last 50 autism patients evaluated with trio whole genome sequencing (trio-WGS). “Qualified” variants were defined as coding, very rare, and evolutionarily conserved. Primary Diagnostic Variants (PDV) additionally were in genes directly linked to ASD.
A PDV was identified in 34/50 (68%) of cases, including 25 (50%) heterozygous de novo, 3 X-linked, 4 autosomal recessive, 2 autosomal dominant, and 1 heteroplasmic mtDNA variants. De novo variants in genes associated with ASD were far more likely to be Qualified than non-Qualified (control group, P = 0.002), validating that most are indeed disease causal. Only 14/34 (41%) of PDV cases had the variant listed on the laboratory report, and reanalysis increased diagnostic yield from 28% to 68%. The “missed” cases predominately included genes with zero (14 cases) to ≤5 prior reported case reports. Many cases both with and without a PDV had inherited Qualifying variants in known ASD-associated genes, suggesting polygenic inheritance. Thirty-three participants (66%) had treatment recommendation(s) based on DNA analyses.
Our results demonstrate high yield of trio-WGS for revealing molecular diagnoses in ASD that is greatly enhanced by re-analyzing DNA sequencing files. Many are de novo and represent un/under-published conditions.
Keywords
autism spectrum disorder; diagnostic yield; DNA sequencing; novel disorders
Subject
Medicine and Pharmacology, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
