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

Scientists studied quadruplets (four children born together) where only one child had autism. They compared the DNA of all four children and their parents to find genetic differences that might explain why one child developed autism. They found two new genes (TRAM2 and DGKD) that may be linked to autism. These genes are involved in how brain cells communicate with each other and how the brain develops. This is the first time researchers have studied quadruplets to understand autism genetics.

This study examined the genetic profiles of quadruplets where only one child had autism spectrum disorder (ASD), representing the first genetic study of quadruplets in autism research. Using whole exome sequencing on the quadruplets and their parents, researchers identified 218 autism-specific genetic variants in the affected child. Two novel candidate genes were discovered: TRAM2 (with a homozygous variant) and DGKD (with compound heterozygous variants), both predicted to be harmful. The genetic variants found were enriched in biological processes related to synaptic transmission and brain development, supporting current understanding of autism's neurobiological basis.

This unique family structure provides valuable insights into potential genetic causes of autism.

Discovery of TRAM2 and DGKD as potential autism genes may inform future genetic testing panels and therapeutic targets. However, clinical application requires validation in larger studies. The enrichment of variants in synaptic and neurodevelopmental pathways supports targeted research in these areas.

Single family study with small sample size. Novel candidate genes require replication in larger populations. Clinical significance of identified variants needs functional validation. Limited generalizability from one quadruplet family to broader autism population.

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.