Prevalence and Phenotypic Impact of Rare Likely Pathogenic Variants in Autism Spectrum Disorder

Abstract Background: Copy number variants (CNVs) and single nucleotide variants (SNVs) are sources of risk for autism spectrum disorder (ASD). The distribution of such pathogenic variants in individuals with ASD and the characterization of those who carry such variants versus those who do not are understudied at the population level. We describe a population sample from Sweden, evaluating the distribution of likely pathogenic variants and their impact on medical, neurological, and psychiatric phenotypes.Methods: The genotyped sample consisted of 1,236 children born in Sweden with autistic disorder, a severe form of ASD (International Classification of Diseases, Tenth Revision, code F84.0.) Of these individuals, CNVs were called from 997, while SNVs were called from 808. Results: Out of 997 individuals from whom CNVs were called, 104 (10.4 %) carried one or more likely pathogenic CNV, including 15q11q13 (n=8), 15q13.3 (n=5), 16p13.11 (n=5), 16p11.11 (n=5), 22q11.2 (n=5). Of 808 individuals assessed by whole-exome sequencing, 69 (8.5%) had a likely pathogenic SNV, including in GRIN2B (n = 6), POGZ (n = 5), SATB1 (n=4), DYNC1H1 (n=4), and CREBBP (n=3). Fourteen individuals carried two likely pathogenic CNVs, and 5 carried a likely pathogenic CNV and SNV. Carriers of likely pathogenic CNVs or SNVs were more likely to have intellectual disability (ID), scholastic skill disorders, and epilepsy, with odds ratios of 2.31 (95%CI, 1.55,3.47), 1.98 (95%CI, 1.19,3.21), and 1.63 (95%CI, 1.08,2.44) respectively. Carriers of likely pathogenic CNVs also showed significant increased rates of congenital anomalies. We compared rates of likely pathogenic CNVs, SNVs, and phenotypes from genotyped AD subjects with and without ID: rates were not significantly different between groups. Limitations: As a case-control cohort, we did not have de novo information to aid in classification. More broadly, there were judgment calls involved in identifying likely pathogenic variants. For these reasons, some misclassification is possible. In addition, phenotypes are defined from medical registers, which may lead to underestimates of milder findings.Conclusions: People with ASD who carry likely pathogenic CNVs or SNVs show increased rates of various comorbidities, most prominently ID. Despite the strong association with ID, conditioning on its presence explains little of the variation for other comorbidities and physical traits.