@article {Torrico350, author = {B{\`a}rbara Torrico and Alex D. Shaw and Roberto Mosca and Norma Viv{\'o}-Luque and Amaia Herv{\'a}s and No{\`e}lia Fern{\`a}ndez-Castillo and Patrick Aloy and M{\`o}nica Bay{\'e}s and Janice M. Fullerton and Bru Cormand and Claudio Toma}, title = {Truncating variant burden in high-functioning autism and pleiotropic effects of LRP1 across psychiatric phenotypes}, volume = {44}, number = {5}, pages = {350--359}, year = {2019}, doi = {10.1503/jpn.180184}, publisher = {Journal of Psychiatry and Neuroscience}, abstract = {Background: Previous research has implicated de novo and inherited truncating mutations in autism-spectrum disorder. We aim to investigate whether the load of inherited truncating mutations contributes similarly to high-functioning autism, and to characterize genes that harbour de novo variants in high-functioning autism.Methods: We performed whole-exome sequencing in 20 high-functioning autism families (average IQ = 100).Results: We observed no difference in the number of transmitted versus nontransmitted truncating alleles for high-functioning autism (117 v. 130, p = 0.78). Transmitted truncating and de novo variants in high-functioning autism were not enriched in gene ontology (GO) or Kyoto Encyclopedia of Genes and Genomes (KEGG) categories, or in autism-related gene sets. However, in a patient with high-functioning autism we identified a de novo variant in a canonical splice site of LRP1, a postsynaptic density gene that is a target for fragile X mental retardation protein (FRMP). This de novo variant leads to in-frame skipping of exon 29, removing 2 of 6 blades of the β-propeller domain 4 of LRP1, with putative functional consequences. Large data sets implicate LRP1 across a number of psychiatric disorders: de novo variants are associated with autism-spectrum disorder (p = 0.039) and schizophrenia (p = 0.008) from combined sequencing projects; common variants using genome-wide association study data sets from the Psychiatric Genomics Consortium show gene-based association in schizophrenia (p = 6.6 {\texttimes} E-07) and in a meta-analysis across 7 psychiatric disorders (p = 2.3 {\texttimes} E-03); and the burden of ultra-rare pathogenic variants has been shown to be higher in autism-spectrum disorder (p = 1.2 {\texttimes} E-05), using whole-exome sequencing from 6135 patients with schizophrenia, 1778 patients with autism-spectrum disorder and 7875 controls.Limitations: We had a limited sample of patients with high-functioning autism, related to difficulty in recruiting probands with high cognitive performance and no family history of psychiatric disorders.Conclusion: Previous studies and ours suggest an effect of truncating mutations restricted to severe autism-spectrum disorder phenotypes that are associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.}, issn = {1180-4882}, URL = {https://www.jpn.ca/content/44/5/350}, eprint = {https://www.jpn.ca/content/44/5/350.full.pdf}, journal = {Journal of Psychiatry and Neuroscience} }