The Genetic Architecture of Autism Spectrum Disorders in the Faroe Islands
Autism spectrum disorders (ASD) are a group of neuropsychiatric disorders characterized by deficits in social communication, as well as presence of restricted interests, stereotyped and repetitive behaviors. The biological causes of ASD remain largely unknown mostly because of the clinical and genetic heterogeneity of this complex condition.
This project aims to characterize the genetic architecture of ASD in the Faroe islands located between the Norwegian Sea and the North Atlantic Ocean, approximately half distance from Norway and Iceland.
We obtained the genetic profiles of 380 individuals from the Faroe Islands (36 patients with ASD, 129 relatives and 215 controls) using genome-wide genotyping of >5 millions SNPs and whole-exome sequencing.
We first analysed the contribution of de novo mutations (CNVs, SNVs and indels) in 28 patients with ASD. For 3 patients, we identified de novo mutations in known ASD-risk genes/loci : 1 22q11.1 deletion, 1 deletion of NRXN1, and 1 damaging MECP2 missense mutation. We also identified inherited rare exonic CNVs and SNVs altering genes previously associated with ASD (ADNP, BCL9, IMMP2L, TBL1X, TBL1XR1, ACACA, ROBO1, RARS2 and ALDH3A2). As expected, we observed a relatively higher homozygosity compared to other world-wide populations (P<0.0001). Interestingly, patients with ASD had a slightly higher inbreeding coefficient compared with controls (FASD=0.007; FControls= -0.004; P=0.0002), suggesting that, in a subset of patients, recessive mutations could contribute to the increase risk of having ASD. In a consanguineous family, we found a rare homozygous missense variant affecting KIRREL3, a member of the nephrin-like protein family. Finally, our analysis also revealed new compelling candidate genes for ASD such as IQSEC3, a guanine nucleotide exchange factor highly expressed in the brain, RIMS4, a key regulator for neuronal arborisation and SMG7, a gene involved in mRNA non-sense mediated decay.
In summary, we identified deleterious mutations in known ASD-risk genes in 36% of the patients indicating that the genetic architecture of ASD in the Faroe Islands might not be very different from other populations. Remarkably, recessive mutations might not increase dramatically the risk of ASD in the genetic isolate. Further analyses are currently in progress to better understand the interplay between the common and the rare variants in the susceptibility and the severity of ASD in these patients.