Researchers have identified ultra-rare, likely gene-disruptive variants unique to autism families, revealing 28 novel candidate risk genes.
The genetics of autism spectrum disorder
Estimated to affect 1 in 160 children worldwide, autism spectrum disorder is a phenotypically diverse developmental disorder. Affected individuals display difficulties in social interaction and communication. The type and severity of symptoms are highly varied among affected individuals.
The exact causes of autism are unknown, but scientific evidence has implicated a range of genetic and environmental risk factors. One of the most significant genetic contributors is de novo mutation (DNM) variation, explaining ~3-25% of cases. DNMs are extremely rare genetic alterations that occur in individuals but are not seen in either parent. In autism research, studying DNMs has driven the discovery of most risk genes.
However, DNMs do not account for most autism cases, especially for multiplex families with more than one affected child. Corroborating with the high heritability of autism, recent studies have implicated common inherited risk variants. These suggest that other non-DMN classes of genetic variation may also contribute to autism risk.
Identifying private transmitted variants
In this study recently published in Nature Genetics, researchers from the University of Washington School of Medicine analysed private inherited variants contributing to autism risk. These are ultra-rare, heterozygous variants observed once in the parent population and transmitted to at least one child.
To identify private inherited variants, the researchers generated a highly sensitive variant callset by merging 2 whole-genome sequencing (WGS) datasets. They generated the first dataset by sequencing 645 families with multiplex or simplex autism (one affected child). The second was derived from WGS data of 3,474 affected families from the Centers for Common Disease Genomics.
The researchers restricted their analyses to autosomal, protein-coding genomic regions in order to increase the power to detect enrichment of private transmitted variants in affected children (probands). Of these, they focused on likely-gene disruptive (LGD) variants. LGDs are defined in this study as stop-gain, stop-loss, splice-altering single nucleotide variants or frameshift indels.
Private transmitted LGD variants were shown to be enriched in probands. Their effect size was estimated to be about 8-fold smaller compared to DNMs. Nevertheless, the analysis revealed that private LGD variants contribute to at least 4.5% autism risk in the human population.
Novel autism risk genes
After excluding genes known to be enriched in DNMs in autism and neurodevelopmental disorders, 95.4% of the private transmitted LGD variant burden remained in probands.
These variants resided in 163 genes. In total, the researchers observed 28 genes with independent LGD variants in 2 or more unrelated families.
These included a small network of genes in the E3 ubiquitin ligase pathway. Another set of genes were involved in intracellular transport, a process important for the transport of synaptic molecules. Previously, several genes in both processes have been shown to be enriched in DNMs and other mutations in children with autism. These findings suggest that DNMs and private transmitted LGD variants converge on the same pathways but affect distinct genes.
Unlike DNMs, private LGD variants have not previously been studied in the context of autism. Yet, this study has shown that most of the LGD variant burden lies outside of genes enriched for DNMs, revealing new gene candidates underlying autism risk. This highlights the value of analysing classes of genetic variation when discovering risk loci for complex diseases.
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