Whole Exome Sequencing Study of a Multizygotic Quadruplet Discordant for Autism Spectrum Disorder Reveals Novel Autism Candidate Genes

Autism spectrum disorder (ASD) is a childhood-onset complex neurodevelopmental disorder. We carried out a comprehensive genetic study of a quadruplet discordant for ASD to identify the candidate genes of ASD. Whole exome sequencing (WES) was done for the quadruplet and their parents. We identified 218 proband-specific de novo single nucleotide variants (SNVs) and 100 indels, none of which were deleterious. Among these, nine SNVs and six indels are reported in autism databases. A homozygous recessive non-synonymous SNV in TRAM2, and a pair of compound heterozygous non-synonymous SNVs in DGKD, all of which were proband-specific, were predicted to be deleterious. These are novel candidate genes for ASD. Genes harboring proband-specific de novo and inherited variants were enriched in the biological processes related to synaptic transmission and neurodevelopment. This is the first genetic study of a quadruplet in ASD.