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Diagnostics Genetics and epigenetics

The Genes of the Spectrum

The role that genetics plays in autism spectrum disorders (ASD) has been investigated for decades, but with our understanding of autism – and neurodivergence as a whole – constantly evolving, what is the current view of genetics and its relationship to ASD?

It’s not news that some genes are associated with autism but, so far, many investigations into autism genetics have focused on variants not inherited from parents. To combat this (and to create a much more accurate picture of ASD genetic risk), one team combined both de novo and inherited variants across a wide pool of cases (1). The team used SPARK (Simons Powering Autism Research), an online platform on which individuals across the autism spectrum can offer their genetic data, giving researchers access to a total of 42,607 cases.

The large cohort of autistic individuals led to the identification of five new risk genes – NAV3, ITSN1, SCAF1, HNRNPUL2, and MARK2. The data show that autistic people who have inherited loss-of-function in the first four of these genes have lower levels of cognitive impairment comorbidities than individuals without such alterations.

Elsewhere, another team has also addressed the focus on de novo variants by exploring mutations rarely observed in non-autistic individuals (2). The team analyzed more than 60,000 cases using joint analysis of protein-truncating variants (PTVs), missense variants, and copy number variants (CNVs) – ultimately leading to the discovery of 72 ASD gene associations. De novo PTVs, damaging missense variants, and CNVs made up 57.5, 21.1, and 8.44 percent of the evidence, respectively. Meanwhile, CNVs conferred greatest relative risk.

The team also conducted meta-analysis alongside individuals who presented with developmental delay. This effort led to the identification of 373 genes associated with both ASD and developmental delay, though relative frequency of these mutations differed between groups. Interestingly, the genes associated with ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes. What future research will focus on – and where researchers come to a roadblock – is making sense of the wide overlap between genes associated with ASD and other neurodevelopmental disorders and what pathways exist between them.

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  1. X Zhou et al., “Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes,” Nat Genet, 54, 1305 (2022). PMID: 35982159.
  2. JM Fu et al., “Rare coding variation provides insight into the genetic architecture and phenotypic context of autism,” Nat Genet 54, 1320 (2022). PMID: 35982160.
About the Author
George Francis Lee

Deputy Editor, The Pathologist

Interested in how disease interacts with our world. Writing stories covering subjects like politics, society, and climate change.

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