JPBS

Chromosomal microarray (CMA) has been suggested for first tier clinical diagnostic test for ASD, with hundreds of genes being associated with ASD by High-throughput Sequencing (HTS). Whole Exome Sequencing (WES) was used to combine with CMA to identify clinical relevant variants in ASD. In our previous work, we used trio (father, mother and proband) based WGS (Whole Genome Sequencing) to reveal clinical relevant de novo or inherited rare variants in half (16/32) of ASD families which all probands have normal or VOUS (Variant of Uncertain Clinical Significance) CMA results. In this study, after screening the chromosome structural abnormalities of a proband affected with ASD by CMA, WES was performed on the patient and the parents, and some rare de novo or inherited rare variants have been detected using trios based bioinformatics analysis. To evaluate the variants in ASD, we rank the variants by SFARI Gene score, HPO (Human Phenotype Ontology) and protein function damaging, manual searching PubMed, and we also validated some of candidate variants in other members in this family by Sanger sequencing. We confirmed a de novo homozygous mutation in SPG11 (p.C209F), two inherited compound heterozygote mutations in SCN9A (p.Q10R and p.R1893H) and BEST1 (p.A135V and p.A297V). We also confirmed heterozygous mutations in TSC1 (p.S487C) and SHANK2 (p.Arg569His) inherited from mother.