The number of genes associated with autism is increasing, but few studies have been performed on epidemiological cohorts and in isolated populations. Here, we investigated 357 individuals from the Faroe Islands including 36 individuals with autism, 136 of their relatives and 185 non-autism controls. Data from SNP array and whole exome sequencing revealed that individuals with autism had a higher burden of rare exonic copy-number variants altering autism associated genes (deletions (p = 0.0352) or duplications (p = 0.0352)), higher inbreeding status (p = 0.023) and a higher load of rare homozygous deleterious variants (p = 0.011) compared to controls. Our analysis supports the role of several genes/loci associated with autism (e.g., NRXN1, ADNP, 22q11 deletion) and identified new truncating (e.g., GRIK2, ROBO1, NINL, and IMMP2L) or recessive deleterious variants (e.g., KIRREL3 and CNTNAP2) affecting autism-associated genes. It also revealed three genes involved in synaptic plasticity, RIMS4, KALRN, and PLA2G4A, carrying de novo deleterious variants in individuals with autism without intellectual disability. In summary, our analysis provides a better understanding of the genetic architecture of autism in isolated populations by highlighting the role of both common and rare gene variants and pointing at new autism-risk genes. It also indicates that more knowledge about how multiple genetic hits affect neuronal function will be necessary to fully understand the genetic architecture of autism.

与自闭症相关的基因数量正在增加，但是对流行病学队列研究和孤立人群的研究很少。在这里，我们调查了法罗群岛（Faroe Islands）的357位个体，其中包括36位自闭症患者，136位亲戚和185位非自闭症控制者。来自SNP阵列和整个外显子组测序的数据表明，患有自闭症的人承担改变自闭症相关基因（缺失（p  =  0.0352）或重复（p  =  0.0352））的稀有外显子拷贝数变异的负担较高，近交状态较高（p  =  0.023）和较高的稀有纯合子有害变异体负载（p  = 0.011）与对照组相比。我们的分析支持与自闭症相关的几种基因/位点（例如，NRXN1，ADNP，22q11缺失）的作用，并鉴定出新的截短（例如，GRIK2，ROBO1，NINL和IMMP2L）或隐性有害变体（例如，KIRREL3和CNTNAP2）影响自闭症相关基因。它还揭示了与突触可塑性有关的三个基因：RIMS4，KALRN和PLA2G4A。，在没有智力障碍的自闭症患者中携带从头开始的有害变体。总而言之，我们的分析通过强调常见和稀有基因变体的作用并指出新的自闭症风险基因，从而更好地理解了孤独症人群的自闭症遗传结构。它还表明，需要更多的关于多种基因突变如何影响神经元功能的知识，才能充分理解自闭症的遗传结构。