High Sensitivity for Detection of Primary Diagnostic Variants in Autism, Including De Novo Variants, with Trio Whole Genome Sequencing and Data Reanalysis

• DOI: 10.20944/preprints202308.1002.v1
• Publication Date: 2023-08-15T00:40:45Z
• Authors: Omri Bar; Elizabeth Vahey; Mark Mintz; Richard E. Frye; Richard G. Boles

Autism spectrum disorder (ASD) is a common condition with lifelong implications and strong hereditary component suggesting genetic underpinnings. The last decade has seen dramatic improvements in DNA sequencing, bioinformatics, databases. 
 We analyzed the raw sequencing files on Variantyx® (Framingham, MA, USA) bioinformatics platform for 50 autism patients evaluated trio whole genome (trio-WGS). “Qualified” variants were defined as coding, very rare, evolutionarily conserved. Primary Diagnostic Variants (PDV) additionally genes directly linked to ASD.
 A PDV was identified 34/50 (68%) of cases, including 25 (50%) heterozygous de novo, 3 X-linked, 4 autosomal recessive, 2 dominant, 1 heteroplasmic mtDNA variants. De novo associated ASD far more likely be Qualified than non-Qualified (control group, P = 0.002), validating that most are indeed disease causal. Only 14/34 (41%) cases had variant listed laboratory report, reanalysis increased diagnostic yield from 28% 68%. “missed” predominately included zero (14 cases) ≤5 prior reported case reports. Many both without inherited Qualifying known ASD-associated genes, polygenic inheritance. Thirty-three participants (66%) treatment recommendation(s) based analyses.
 Our results demonstrate high trio-WGS revealing molecular diagnoses greatly enhanced by re-analyzing files. represent un/under-published conditions.