Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed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. 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. Preprints 2023, 2023081002. 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

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