Genetic Variant Analyses Identify Novel Candidate Autism Risk Genes from a Highly Consanguineous Cohort of 104 Families from Oman

Abstract

Deficits in social communication, restricted interests, and repetitive behaviours are hallmarks of autism spectrum disorder (ASD). Despite high genetic heritability, the majority of clinically diagnosed ASD cases have unknown genetic origins. We performed genome sequencing on mothers, fathers, and affected individuals from 104 families with ASD in Oman, a Middle Eastern country underrepresented in international genetic studies. This approach identified 48 novel candidate genes significantly associated with ASD in Oman. In particular, 35 of these genes have been previously implicated in neurodevelopmental disorders (NDDs) in other populations, underscoring the conserved genetic basis of ASD across ethnicities. Genetic variants within these candidate genes that would impact the encoded protein included 1 insertion, 4 frameshift, 6 splicing, 12 nonsense, and 67 missense changes. Notably, 61% of the SNVs were homozygous, suggesting a prominent recessive genetic architecture for ASD in this unique population. The scarcity of genetic studies on ASD in the Arabian Peninsula has impeded the understanding of the unique genetic landscape of ASD in this region. These findings help bridge this knowledge gap and provide valuable insights into the complex genetic basis of ASD in Oman.

Keywords: autism spectrum disorder (ASD); candidate ASD risk genes; genome sequencing (GS); variant of unknown significance (VUS).

Figure 1

Summary of 104 ASD individuals and their GS results. (A) Sex distribution of participants; (B) number of consanguineous families; (C) counts of known and novel genes identified; (D) types of genetic variants identified; (E) inheritance patterns of the variants.

Figure 2

STRING interaction enrichment analysis identified two dominant enrichment networks as denoted by red (synaptic membranes—(A)) and yellow nodes (ubiquitin pathway—(B)). Coloured nodes represent query proteins and the first shell of interactions, connected by coloured lines indicating the known interactions derived from experimental data, curated databases, co-expression studies, or text-mining. Blue lines denote known interactions from curated databases, pink lines represent experimentally determined interactions, black lines indicate co-expression, and purple lines signify homology.