Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic influences. There is an increasing demand for ASD genetic testing beyond the traditionally recommended microarray and syndromic autism testing; however, the current whole genome sequencing (WGS) and whole exome sequencing (WES) methods are lacking an academic standard for WGS variant annotation, reporting, and interpretation, tailored towards patients with ASD and offer very limited interpretation for clinical significance. Using WGS data from six family trios, we demonstrate the clinical feasibility and technical implementation of an evidence-based, fully transparent bioinformatics pipeline and report framework for an ASD-focused WGS genetic report. We confirmed a portion of the key variants with Sanger sequencing and provided interpretation with consideration of patients’ clinical symptoms and detailed literature review. Furthermore, we showed that identification of the genetic contributions of ASD core symptoms and comorbidities may promote a better understanding of the ASD pathophysiology, lead to early detection of associated comorbidities, and facilitate pharmacologic intervention based on pathological pathways inferred from the genetic information. We will make the bioinformatics pipeline and interpretation framework publicly available, in an easily accessible format, after validation with a larger cohort. We hope that the present proposed protocol can serve as a starting point to invite discourse and debate to further improve approaches in WGS-based genetic consultation for patients with ASD.
Highlights
Many of the variants are associated with ion channels, including SLC12A5, SLCO1B1, SLC7A14, and GJB2, which is consistent with current research that shows chanopathies are an important pathogenic driver of Autism spectrum disorders (ASD) [21]
We applied this pipeline to the sequencing data of an ASD trio who visited the clinic in November 2021 and quickly identified a pathogenic variant within the PAH
We propose a genetic report framework tailored to patients with ASD that contains evidence-based results with the goal to provide a detailed explanation and actionable guidance to patients (Figure 3)
Summary
The field of personal genomics is moving at an unprecedented pace, which is driven in part by reduction in the cost of generation sequencing (NGS) technology and continuous expansion of databases correlating variants with clinical phenotypes [1]. Recent reports show that as many as 20% of participants in predispositional sequencing cohorts may have a variant with monogenic disease risk [2]. ASD can be broadly classified as syndromic or non-syndromic. The pathogenesis of non-syndromic ASD is thought to originate from complex interactions between environmental factors, such as environmental toxin exposure, prenatal infections, autoimmune conditions, as well as gut microbiome abnormalities, and genetic predispositions [6,7,8]. As of January 2021, the Simons Foundation Autism Research Initiative (SFARI)
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