Identifying Rare Genetic Variants of Immune Mediators as Risk Factors for Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) affects more than 1% of children, and there is no viable pharmacotherapeutic agent to treat the core symptoms of ASD. Studies have shown that children with ASD show changes in their levels of immune response molecules. Our previous studies have shown that ASD is more common in children with folate receptor autoantibodies. We also found that children with ASD have abnormal gut immune function, which was characterized by a significant increase in the content of immunoglobulin A and an increase in gut-microbiota-associated epitope diversity. These studies suggest that the immune mechanism plays an important role in the occurrence of ASD. The present study aims to systematically assess gene mutations in immune mediators in patients with ASD. We collected genetic samples from 72 children with ASD (2–12 years old) and 107 healthy controls without ASD (20–78 years old). We used our previously-designed immune gene panel, which can capture cytokine and receptor genes, the coding regions of MHC genes, and genes of innate immunity. Target region sequencing (500×) and bioinformatics analytical methods were used to identify variants in immune response genes associated with patients with ASD. A total of 4 rare variants were found to be associated with ASD, including HLA-B: p.A93G, HLA-DQB1: p.S229N, LILRB2: p.R322H, and LILRB2: c.956-4C>T. These variants were present in 44.44% (32/72) of the ASD patients and were detected in 3.74% (4/107) of the healthy controls. We expect these genetic variants will serve as new targets for the clinical genetic assessment of ASD, and our findings suggest that immune abnormalities in children with ASD may have a genetic basis.

Binding Folate Receptor Alpha Autoantibody Is a Biomarker for Leucovorin Treatment Response in Autism Spectrum Disorder

“…The effect of FRAAs on ASD severity has been investigated [29][30][31][32]. One study found that those with blocking FRAAs had more favorable development and metabolic profiles than those with binding FRAAs, and those with binding FRAAs had higher B12 concentrations in the blood than those with blocking FRAAs [33].…”

Assessment of rare genetic variants to identify candidate modifier genes underlying neurological manifestations in neurofibromatosis 1 patients

“…Given the small sample size of our study, failing to pass the Bonferroni correction threshold could be expected, thus all genes with a p < 0.005 in the SKAT-O analysis were moved forward to functional follow-up. Setting the threshold at p < 0.005 for SKAT-O analysis could provide signi cant ndings of rare variants, and many studies have already identi ed interesting signals using a higher p-value threshold in SKAT-O analysis [29][30][31]. Further, there was a lack of functional studies and modi er gene validations.…”

Assessment of Rare Genetic Variants to Identify Candidate Modifier Genes Underlying Neurological Manifestations in Neurofibromatosis 1 Patients

“…Given the small sample-size of our study, failing to pass the Bonferroni correction threshold could be expected, thus all genes with a p < 0.005 in the SKAT-O analysis were moved forward to functional follow-up. Setting the threshold at p < 0.005 for SKAT-O analysis could provide significant findings of rare variants, and many studies have already identified interesting signals using a higher p -value threshold in SKAT-O analysis [ 36 , 37 , 38 ]. Further, there was a lack of functional studies and modifier gene validations.…”